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Review

Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review

by
Luka Katic
1,2,* and
Anamarija Priscan
3
1
Department of Medicine, Icahn School of Medicine at Mount Sinai Morningside/West, 1000 Tenth Avenue, New York, NY 10019, USA
2
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
3
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2023, 13(10), 1490; https://doi.org/10.3390/biom13101490
Submission received: 25 August 2023 / Revised: 2 October 2023 / Accepted: 6 October 2023 / Published: 7 October 2023
(This article belongs to the Section Molecular Medicine)
Browse Figures
Review Reports Versions Notes

Abstract

:
This review commemorates the 10-year anniversary of the discovery of physiological ligands Augα (Augmentor α; ALKAL2; Fam150b) and Augβ (Augmentor β; ALKAL1; Fam150a) for anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK), previously considered orphan receptors. This manuscript provides an in-depth review of the biophysical and cellular properties of ALK family receptors and their roles in cancer, metabolism, pain, ophthalmology, pigmentation, central nervous system (CNS) function, and reproduction. ALK and LTK receptors are implicated in the development of numerous cancers, and targeted inhibition of their signaling pathways can offer therapeutic benefits. Additionally, ALK family receptors are involved in regulating body weight and metabolism, modulating pain signaling, and contributing to eye development and pigmentation. In the CNS, these receptors play a role in synapse modulation, neurogenesis, and various psychiatric pathologies. Lastly, ALK expression is linked to reproductive functions, with potential implications for patients undergoing ALK inhibitor therapy. Further research is needed to better understand the complex interactions of ALK family receptors and Aug ligands and to repurpose targeted therapy for a wide range of human diseases.

1. Introduction

This review marks the 10-year anniversary of the discovery of physiological ligands Augα (Augmentor α; ALKAL2; Fam150b) and Augβ (Augmentor β; ALKAL1; Fam150a) for anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK), which were previously considered orphan receptors [1]. While small-molecule ALK inhibitors that target the intracytoplasmic kinase domain by binding to the ATP-binding site have been extensively studied and used for cancer treatment, their repurposing for other pathologies, such as neurological, cardiac, and metabolic diseases, has proven challenging [2,3,4]. Given their need to be lipophilic to cross the cell lipid bilayer and bind intracellularly, this class of drugs is prone to toxicities [5]. Moreover, the structural similarities between the ATP binding sites of kinase domains in the entire family of receptor tyrosine kinases (RTKs) make these drugs relatively non-specific, increasing the possibility of off-target binding and side effects [5].
Monoclonal antibodies that target ALK receptors offer an alternative approach, as they are highly specific, generally non-toxic, and can fine-tune signaling. By blocking ligand binding or promoting dimerization, monoclonal antibodies have the potential to modulate ALK signaling pathways for therapeutic benefit in non-cancerous pathologies [6,7,8,9]. They generally do not cross the lipid bilayer or the blood-brain barrier [10]. Activating analogs of a ligand can be used as an agonist to bind to the ligand binding site [11]. This review will focus on the physiological relevance of ALK-Augα and LTK-Augβ signaling and encourage further research efforts toward the repurposing of monoclonal antibodies, Aug analogs, and TKIs to modulate these mechanisms of action.

2. Biophysical and Cellular Background

The receptor tyrosine kinase field encompasses 20 families, comprising approximately 55 known receptors to date [12]. Its beginnings can be traced back to the 1970s [13], and since then, significant advancements have been made. These include gaining biophysical structural understanding, identifying receptor functions (such as proliferation, differentiation, survival, and metabolism), and developing a wide range of therapeutic agents that modulate RTK functions, many of which have been approved by the FDA or are currently in clinical trials [12].
A typical receptor features an extracellular domain, a single transmembrane helix, and an intracellular domain. When a growth factor binds to the extracellular domain, it activates signaling through the induction of dimerization. The self-association of two receptors then propagates to the intracellular part, where the tyrosine kinase domains phosphorylate one another. In all activated RTKs, the activation loop within the N lobe of the TKD undergoes a conformational shift from a cis-autoinhibited state to a trans-phosphorylation-prone state, ultimately leading to the opening of the ATP binding sites within the kinase domain, which, in turn, induces trans-phosphorylation and activation [12].
Over the past several decades, extensive research has been conducted on receptor tyrosine kinases (RTKs), leading to the identification of most RTK ligands. However, the ALK family remained an exception [1,12]. This family consists of only two receptors: ALK and LTK [14,15]. These receptors share striking similarities in their structure, including an intracellular kinase domain, a transmembrane helix, and an extracellular part. In the extracellular region, the C-terminal portion is conserved between the two receptors, featuring an EGF-like domain, a glycine-rich region, and a TNF-like domain. Additionally, ALK possesses a distinctive N-terminal segment comprising two MAM domains, an LDLa-like region between them, and an N-terminal heparin-binding region [16,17,18,19,20].
In lower evolutionary species, the ALK family has only one receptor, ALK [19]. The LTK receptor likely originated from gene duplication in vertebrates, with lower evolutionary vertebrates possessing the unique N-terminal part [19]. However, in mammals, the N-terminal portion of LTK is absent. The ALK phylogenetic tree reveals that lower evolutionary species such as D. melanogaster [21] and C. elegans [22] maintain the N-terminal part, resembling the human structure, while some vertebrates, like D. rerio, have lost portions of the N-terminal region of the ALK receptor [23]. Intriguingly, the N-terminal part of human ALK is proteolytically processed in the brain but not in dorsal root ganglia (DRG) neurons [24]. Matrix metalloproteinase 9 (MMP9) mediates this proteolytic processing (shedding) of ALK’s N-terminal region [25].
The initial ALK ligands identified were for D. melanogaster’s ALK (dALK) and C. elegans’s ALK (SCD-2). The ligand for dALK is Jeb (Jelly Belly), while the ligand for SCD-2 is Hen-1 (Hesitation Behavior 1). Interestingly, both ligands possess an LDLa-like domain. Hen-1 is associated with mediating learning, whereas Jeb is involved in promoting visceral muscle fusion. Nevertheless, neither ligand binds to the vertebrate ALK family, and no vertebrate homologs have been discovered [26,27,28] (Figure 1).
The first suggested human ALK ligand was long-chain heparin (as well as other glycosaminoglycans). This was because heparin triggered ALK phosphorylation in neuroblastoma (NB) cells, but it failed to activate ALK in 3T3 cells. These findings implied that another unidentified factor might be necessary, in conjunction with heparin, to induce ALK activation [16].
In 2014, a screening of 3191 extracellularly secreted proteins revealed that Fam150b (Augα) and Fam150a (Augβ) function as ligands for the LTK receptor. LTK phosphorylation increased more than 30-fold with Augβ and over two-fold with Augα compared with the control. Interestingly, IGF-2 also elevated LTK phosphorylation above baseline but with significantly weaker potency [1]. No homologs of Augs have been found in non-vertebrate species, and no homologs of Jeb or Hen-1 have been identified in vertebrate species [29].
The discovery of Augs in the LTK screen was later applied to ALK. Both Augs were found to induce ALK phosphorylation when co-expressed in cells, an effect that was reversible upon ALK inhibition using the tyrosine kinase inhibitor (TKI) crizotinib and the ALK-specific monoclonal antibody mAb13. Additionally, co-expression of Augs and ALK in Drosophila eye produced an ALK gain-of-function rough eye phenotype, demonstrating in vivo relevance [30].
An examination of the hierarchy and specificity of ALK family receptors and Aug ligands revealed that Augα activated both ALK and LTK at picomolar concentrations, while Augβ only activated LTK at picomolar concentrations and ALK at nanomolar concentrations. The authors also demonstrated that the unique N-terminal part of ALK was not crucial for Aug-induced stimulation, and heparin exhibited synergy only with lower concentrations of Augα [17].
Researchers reported issues with Aug stability, as, being small and basic proteins, they are susceptible to proteolytic cleavage [17,30]. Furthermore, full-size Augα ligands tended to precipitate at concentrations higher than 0.3 mg/mL [18,31]. To address this problem, scientists employed various approaches, ultimately leading to the discovery of a biologically active fragment of Aug. Full-size Augα and Augβ share two distinct regions: an N-terminal variable region (VR) that differs between Augα and Augβ and a C-terminal Aug domain (AD) that is conserved between the two ligands. Four cysteines in the AD region form two intramolecular disulfide bridges. Full-size Augα is expressed as a disulfide dimer, with cysteines at position Cys66 joined together, while full-size Augβ, which lacks an additional cysteine, is expressed as a monomer. Isolating the AD reduced dimer properties, but both truncated and full-size versions of Augα exhibited the same phosphorylation properties, neurite outgrowth properties, and kinetics specific to ALK/LTK [31]. It is currently uncertain whether the variable region (VR) of Augs undergoes physiological processing or if it influences different functions depending on its location or expression.
The three reported ALK family receptor and augmentor structures have been studied by the Kalodimos, Schlessinger, Klein, and Savvides research groups (Table 1). The first two groups propose a 2:2 complex (two receptors with two ligands), while Savvides suggests a 2:1 complex (two receptors with one ligand) [18,19,20].
Savvides’ group first published findings on the isolation of human ALK and LTK ligand-binding segments, and their biophysical analysis using Augβ and Augα fragments. Their results indicate that the 2:1 assembly could be a possible mechanism for LTK-Augβ dimerization and activation. Given the size exclusion chromatography results of the ALK-Augα complex within the study, the possibility that crystallographic conditions may have influenced the results cannot be excluded [19].
A second publication from Kalodimos and Schlessinger’s groups focused on ALK and used full-size Augα ligands, overcoming stability and precipitation issues by mutating Cys66 into hydrophobic tyrosine. Their findings support a 2:2 complex model with four interaction sites. Although the membrane is not incorporated in the complex, the authors propose an additional fourth interaction site where Augα binds to the membrane because of its orientation relative to the EGF-like domain, which points toward the transmembrane segment. The positively charged residues of Augα (Lys95, Lys96, Lys99, His100) could interact with the negatively charged membrane. When these residues are mutated, no ALK phosphorylation is detected in cells. The complex’s structure and interactions suggest that positively charged Augα residues and EGF-like domain bending are crucial for ALK activation [18].
Lastly, a third manuscript by Klein and Schlessinger’s groups used a truncated ALK connected to the Augα AD connected to a linker, resulting in a 2:2 receptor–ligand structure with three interaction sites. Their results indicate that site mutations can impact ALK phosphorylation properties in cells and that certain antibodies can inhibit or activate ALK by binding to specific sites [20].
Research on ALK family receptors and augmentors has produced varying models of their structures and complexes (Figure 2). While some groups propose a 2:2 complex, others suggest a 2:1 complex. Further studies are needed to clarify the discrepancies and better understand the mechanisms of dimerization and activation in these receptors. Furthermore, the function, role, and biophysical properties of ALK’s distinctive N-terminal segment have yet to be fully elucidated.

3. Cancer

The development of cancer through ALK receptor signaling can be initiated by either an ALK fusion protein or a point mutation in the full-length ALK receptor [32]. Notably, the oncogenic activity of the ALK fusion protein, characterized by receptor dimerization and activation, is driven solely by its oligomerization and is entirely independent of any involvement with the ligand Augα [32,33]. EML4 is a common ALK fusion protein that physiologically oligomerizes inside the cell, creating machinery for ALK dimerization and activation. This inherent machinery keeps the protein within the cell, so it is physically impossible for Augα to exert any influence on the activation of the ALK fusion protein [34] A variety of fusion ALK proteins have been reported in numerous cancers, including NSCLC, IMT, and ALCL, with fusions developing almost exclusively on the common breakpoint in exon 20 [32,35]. The ALK locus is particularly prone to chromosomal fusions, and this appears to play a role in both cancer development and evolution [19,35]. TKIs are effective against ALK fusion protein-driven cancers, but resistance and relapse usually occur after initial remission [36,37]. It is often difficult to determine if the receptor mutation is solely causing inhibitor resistance or if it is also contributing to oncogenic activity, as is the case with the ALK-L1198F and ALK-G1201E mutations. They were considered oncogenic, but after the discovery of Augs, these "oncogenic mutants" were tested for a ligand response, and it was found that they do not result in ligand Augα-independent ALK activation [38,39].
Almost exclusively found in neuroblastoma, point mutations have been observed in the full-size ALK receptor, but no fusion proteins have been reported in this type of cancer [32,35]. About 6–12% of all sporadic neuroblastomas are ALK-mutation-positive, with ALK neuroblastoma mutants having three subtypes: ligand-independent, ligand-dependent, or kinase-dead mutants that contain mutations of downstream signaling proteins such as the RAS/MAPK pathway, which includes NF1 mutations and RAF mutations [32]. Although neuroblastoma is strongly associated with altered ALK signaling, ALK gain-of-function mice develop sympathetic ganglia hyperplasia and not cancer, and additional key triggers are necessary for cancer development, typically MYC amplification [40,41,42,43,44]. MYC transcriptional factor drives ALK expression, and ALK signaling drives MYC expression, creating a positive feedback loop [45,46]. MYC-driven neuroblastoma mouse models typically exhibit incomplete penetrance and late onset, as only around 50% of the mice develop cancer within an average of 40 weeks. However, when MYC-driven neuroblastoma mouse models were crossbred with mice that have an ALK gain-of-function mutation (ALK-F1178S), all the mice (98%) developed neuroblastoma within an average of 28 weeks [47]. Clinical trials of neuroblastoma ALK-mutation-positive subgroups treated with crizotinib were not successful, but new, more potent ALK TKIs are now being tested [48]. The discovery of Augs has led scientists to expand the patient subpopulation that could be targeted with ALK inhibitors, as Augα overexpression in mice almost completely reproduces ALK-MYC synergy in driving neuroblastoma [47]. The same synergy is found between MYC-driven neuroblastoma and Augα overexpression, suggesting that inhibitory antibodies might be effective for patient subgroups with ligand misregulation in addition to the potential benefits of ALK TKI treatment [47].
MYC, ALK, and Augα are all located on the 2p chromosome, and the exact 2p gain region is associated with the development of neuroblastoma [49,50]. ALK TKI treatment could be beneficial for all NB patient subtypes with the 2p gain region. An analysis of 356 NB cancer samples showed that 107 patients (30%) had 2p gain (more than four copies) or amplification (more than eight copies), most of which contained Augα, MYCN, and ALK genes [49]. The number of somatic mutations in a significant proportion of NB cases is typically low, and there are no significant hotspot gene mutations. Rather than being driven by mutations, NB seems to be a cancer that is primarily determined by gene copy number [51]. Interestingly, ALK mutation and amplification are prevalent mostly when MYCN is amplified, but Augα amplification is associated with non-MYCN-amplified cases [49]. The Augα/ALK/MYCN signaling axis could be the key relationship between 2p gain and oncogenic activity. Additional evidence supporting this theory is a case report of a 6-month-old boy with poorly differentiated unfavorable NB. After 10 months of chemotherapy, his cancer developed 2p gain and TrkA overexpression [52]. In general, high TrkA expression is a marker for favorable prognosis since it could lead to spontaneous regression, but TrkB expression is a marker of poor prognosis [53]. This patient was started on entrectinib (ALK and Trk inhibitor), improved significantly, and maintained a stable clinical situation more than 5 years after clinical diagnosis [52]. In addition to this case, multiple cases of germline 2p gaining partial trisomy have been reported to trigger NB development [54,55,56].
In addition to 2p gain and MYC amplification, 11q deletion is another significant trigger for NB development [50]. This deletion is believed to remove the tumor suppressor genes DLG2 and SHANK2, which drive neuroblastoma differentiation from proliferation [57,58]. Interestingly, Augα/ALK/MAPK signaling has been shown to both suppress DLG2 transcription and induce NB neurites and differentiation [31,58]. NB can be further classified based on its level of differentiation, with a more benign state having more differentiated adrenergic cells, while a more malignant state resembles neural crest cells and mesenchymal identity [59]. The RTKs TrkA and RET are major drivers of differentiation in these cells [60]. According to Siaw et al. [61], RET expression is high in more differentiated neuroblastoma (NB) cells, while using CRISPR to knock out RET leads to a strong transition toward an undifferentiated mesenchymal state. ALK-positive NB cells activate and phosphorylate RET within minutes of being exposed to Augα, but the RET ligand GDNF does not activate ALK. This activation is reversed by inhibiting ALK or MAPK [61,62]. Lambertz et al. [63], on the other hand, reported that RET signaling occurs through PI3K/AKT/mTOR, but in either case, RET signaling is downstream of ALK [61]. Targeted therapy with joint ALK and RET inhibitors should be used with caution given the complexity of differentiation.
According to a recent study, Augβ was linked to the progression, migration, and invasion of colorectal cancer, as it regulates the Sonic Hedgehog (SHH) signaling pathway that drives tissue polarity and invasion [64]. However, another study failed to detect any Augβ expression in colon cancer cell lines but instead found high levels of both ALK and Augα in cell lines similar to the Consensus Molecular Subtype 1 (CMS1) of colon cancer [65]. This subtype is characterized by DNA mismatch–repair-system-induced mutations, and its growth and proliferation depend on ALK-Augα signaling through the AKT pathway, which can be reversed by Crizotinib (ALK TKI) [65,66]. Interestingly, Crizotinib induces proliferation in cell lines exhibiting CMS-4, suggesting that ALK TKI is not universally beneficial for colon cancer patients [65]. The cancer-reducing effect of ALK TKI on CMS1 was demonstrated in a 3D spheroid model and in a physiologic mouse model, supporting the potential for a clinical trial using combination therapy containing ALK TKI to treat the CMS1 subtype of colon cancer [64,65,66].

4. Metabolism and Body Weight Regulation

The first report of ALK kinase domain deletion in mice demonstrating differences in body weight was published during an investigation of the endogenous role of ALK in the CNS [67]. This study was followed up by GWAS data mining on the healthy Estonian population (Estonian Biobank), which identified a thinness-associated variant located in the first intron of ALK [68]. Knockdown of ALK caused by RNAi in Drosophila reduced triglyceride levels without affecting food intake. ALK knockout mice also displayed a thin phenotype, which was due to sympathetic overactivity and a reduction in fat tissue mass, while lean mass tissue remained intact. To clarify the origin of this thin phenotype, floxing genetic models were used, and ALK was deleted using Cre recombinase from specific tissues: white adipose tissue (AdipoqCre), brown adipose tissue (Ucp1Cre), intestine (VillinCre), liver (AlbuminCre), muscle (MckCre), and hematopoietic cells (Vav1-iCre). However, all of the genetic models failed, but a stereotactic injection of AAV:GFP viral vector containing Cre recombinase into the paraventricular nucleus (PVN) area of a genetically modified mouse containing LoxP sites on the 3’ and 5’ end of the ALK gene displayed a thin phenotype. In this region, neurons containing ALK were preferentially excitatory glutamatergic neurons of pneSS and pneCRH. Other synaptically interconnected neurons that were not mapped were also infected with the virus with subsequent ALK deletion [68]. To further expand the mechanism of signaling, the upstream deletion of potential ALK ligands was generated. Augα knockout mice and Augα/Augβ double-knockout mice displayed a thin phenotype and sympathetic overactivity with only fat tissue mass reduction, while lean muscle mass was preserved. It was proposed that this observed thin phenotype originates from Augα in Agouti-related peptide (AgRP) neurons, which display projections toward PVN. Augα is also upregulated following starvation in AgRP neurons. Other neurons expressing Augα were the paraventricular nucleus (PVN), the dorsomedial nucleus (DMH), and the suprachiasmatic nucleus (SCN). The authors also showed that Augα and ALK signaling are responsible for the pathway and projection development between AgRP neurons and PVN neurons [69].
The regulation of sympathetic activity is also influenced by afferent parasympathetic vagal neurons, which are crucial for transmitting visceral pain and mediating vagal reflexes [70]. Nucleus tractus solitarius (NTS) acts as the second-order neuron for n.vagus afferent projections and has a well-established axonal connection to PVN [71]. There is a strong possibility that the AAV:GFP viral vector used by Orthofer et al. to infect PVN may have also infected NTS axonal projections. Given that Augα is highly expressed in DRG and plays a role in pain signaling [72], investigating its expression in other peripheral ganglia within the autonomic nervous system may shed light on the mechanisms of body weight regulation.
However, inhibiting ALK-Aug signaling to treat obesity may pose a challenge, as small molecular inhibitors of ALK that penetrate the blood–brain barrier can lead to weight gain, hypertriglyceridemia, hypercholesterolemia, and hypertension [73]. For instance, Lorlatinib has been linked to weight gain in children being treated for neuroblastoma [74], and a transcriptome-wide association study has linked the Augα gene to childhood obesity [75]. Furthermore, another brain-penetrating ALK inhibitor, repotrectinib, has also been associated with weight gain [76]. These findings suggest that multiple excitatory and inhibitory neuron groups containing Alk and/or Augα may be involved in weight regulation, adding complexity to the current data evidence.

5. Pain Signaling

Pain is a multifaceted experience involving different types of pain stimuli and nociceptor receptors [77,78]. Based on the etiology, pain sensation can be classified into three subgroups: mechanical, thermal, and chemical pain. Mechanical pain arises from stimuli impacting free nerve endings, TRPA1 receptors, and other similar structures, while thermal pain results from the activation of TRPV1 and TRPM8 receptors and related receptors because of temperature changes. Chemical pain, on the other hand, is triggered by substances that interact with receptors such as TRPV1 and ASIC [78]. The sensitivity and signaling of these nociceptor receptors can be modulated either from the outside of a neuron, for example, during inflammation, or from within a neuron (neuropathy) caused by injury, diabetes, viruses, etc. [78,79] Chronic pain resulting from these modulations is a significant problem for patients, as current treatment options targeting the molecular etiology of the problem are limited [78]. Therefore, an ideal pain treatment should not alter the baseline pain sensation [80]. Behavioral tests have been developed to approximate the pain sensation experienced by mice, including the Von Frey filament assay for mechanical pain and the Hargreaves assay for thermal pain [81].
MAP kinase is a potential molecular target for modulating pathologic pain states, as it highly regulates the ionic channels that initiate and transmit pain, likely through indirect phosphorylation and/or changes in nociceptor transcription and expression [82,83]. Since MAP kinase can be activated by the entire family of receptor tyrosine kinases [12], researchers should focus on spatiotemporal regulation by the MAP kinase and its upstream effector receptor. Augα-ALK interactions drive the MAP kinase pathway and modulate pain signaling. According to the currently proposed mechanism, Augα from the dorsal root ganglia (DRG) stimulates ALK in the spinal cord’s dorsal horn, resulting in pain signaling modulation. Augα is highly expressed in DRGs and is upregulated two-fold following inflammation. Injecting Augα into the spinal cord’s cerebrospinal space stimulates ALK phosphorylation in the dorsal horn, making mice more sensitive to thermal pain. Inhibiting the ALK kinase domain with the blood–brain-barrier-penetrating ALK inhibitor Lorlatinib and depleting Augα with an antisense oligodeoxynucleotide intrathecal injection can prevent inflammation-induced and neuron-injury-induced increased pain sensitization [72]. However, it is unclear if Augα from DRGs creates signals in the synaptic space of the dorsal horn, inducing ALK phosphorylation. Augα is also expressed in the spinal cord, and DRG-primary cultures show signs of having the Augα receptor ALK and/or LTK [24,72]. Augα modulates the DRGs’ ionic channel regulation and its electrophysiological properties, inducing an increased action potential frequency and neurite outgrowth in DRG neurons in response to stimulation [72]. It is possible that two distinct signaling circuits of Augα and ALK signaling exist, one in the DRGs and one in the spinal cord. DRGs are outside the blood–brain barrier, making them an easily targeted location for antibody modulation [84].
The inability of adult neurons to proliferate [85] suggests that the overexpression or mutation of receptor tyrosine kinases driving MAPK signaling may contribute to the development of neuropathic pain [82,83]. A group of isolated cancer patients with neuropathic pain showed a significant response to EGFR inhibitors [86,87], while a meta-analysis of ALK inhibitors intended to treat NSCLC revealed that a subgroup of patients experienced reduced musculoskeletal pain [88]. Anti-NGF monoclonal antibodies (TrkA receptor inhibitors) have shown promise in treating pain and are currently in clinical trials, but a small subset of patients develop rapidly progressive joint degeneration [89]. RET, FGFR1, KIT, InsR, and PDGFRβ are among the other receptors associated with pain modulation within DRGs [90,91,92,93,94], and the understanding of the subtypes of neurons expressing each of these receptors and the spatiotemporal relationship between them driving MAPK in DRGs remains to be elucidated. CRISPR has shown promise as a technique for effectively studying and modulating the epigenome of primary cultured DRGs with a 75% success rate [95].
In addition to nociceptors, DRGs contain neurons with other somatosensory functions, and LTK KO mice show impaired coordination and balance on the rotarod test [96], while dizziness is one of the major symptoms of ALK inhibitors [88]. Augα expression in DRGs [72] suggests that proprioception signaling may also be regulated by Augα and LTK.

6. Ophthalmology and Pigmentation

Numerous clinical cases of patients with ALK-driven cancers who were treated with ALK inhibitors have reported visual impairment as a common side effect, with symptoms such as blurred vision, lowered visual acuity, presbyopia, flashes, and accommodation disorders being strongly correlated with ALK inhibitors [88,97]. In mice, ALK expression has been found in various parts of the eye, including the ciliary ganglia, the neural and pigmental layers of the retina, the lens, and the corneal epithelium [98]. Augα expression has been detected in mice’s nociceptive neurons situated in the dorsal root ganglia (DRG) when they innervate the trunk. It is likely that Augα is also expressed in nociceptive neurons within the trigeminal ganglia, where they are responsible for innervating the eye [72,99]. However, the expression of Augα, Augβ, ALK, and LTK in other autonomic ganglia (sympathetic or parasympathetic), in the context of eye innervation, remains unknown. In Drosophila, ALK and its ligand Jelly Belly play an important role in the development of the visual pathway, as they stimulate projections between the optic lobe from the visual cortex and photoreceptor R8, which are crucial for color vision [100]. This finding has been used to study ALK signaling in vivo, as the ectopic expression of mutated human ALK (F1174S), which has a gain of function, leads to a strong rough eye phenotype [101].
In zebrafish, the homologs of human Augα and Augβ are DrAugαa, DrAugαb, and DrAugβ, which signal through the zebrafish homolog of human LTK, DrLTK, to stimulate eye pigmentation. DrAugαa is critical for truncal-iridophore-induced pigmentation, while DrAugβ is necessary for operculum’s iridophore-induced pigmentation, and both are essential for eye-iridophore-induced pigmentation. At the larval stage, DrAugαa and DrAugαb induce eye iridophore pigmentation, and the interaction of all three zebrafish Augs seems to play a significant role in the eye [23,102]. Interestingly, LTK gain-of-function mutation stimulates iridophore growth and proliferation rather than migration and localization [23,103]. DrLTK has similar extracellular domains as human ALK but shares intracellular kinase domain homology with hLTK. Additional studies are required to clarify the receptor properties of zebrafish LTK and to translate this phenotype into higher evolutionary organisms such as mice.
Neural-crest-derived cells, iridophores, play a crucial role in the coloration of fish at both the larval and adult stages, and LTK, Augα, and Augβ are strongly expressed in these cells [23]. Larval iridophores are directly derived from neural crest cells [104], while adult iridophores arise from stem cells in the dorsal root ganglia [105]. Humans lack iridophores, but melanocytes that induce coloration arise from the neural crest [106]. Recently, LTK expression was linked to the melanoid color variant of amphibian axolotls [107]. In an animal model of uveal melanoma, ALK was found to be positive in all samples, and crizotinib prevented their metastasis [108,109]. Epithelial-cell-type uveal melanomas in humans are more frequently ALK-positive than benign spindle-cell-type cases [108]. However, the expression of LTK and Augs in melanomas is currently unknown. It is necessary to determine the precise role of ALK, LTK, and Augs in neural crest development.

7. CNS and Teratogenicity

For a long time, it has been known that ALK and LTK are expressed in the central nervous system (CNS) [110] ALK is known to play critical roles in modulating the architecture and strength of synapses [111]. Studies on knockout (KO) mice have shown that ALK deficiency leads to a 50% decrease in neurogenesis, whereas LTK deficiency does not have any effect on neurogenesis. Interestingly, ALK-LTK double-KO mice have an 80% decrease in neurogenesis, suggesting that LTK may partially compensate for ALK deficiency. Even though synaptogenesis and neurogenesis are impaired, brain volume remains normal [96]. It is worth noting that, although neurogenesis decreases in these mice, it does not result in any devastating phenotype, as has been observed in viable mice [67,96,112,113].
In contrast, a CNS-penetrable ALK inhibitor, Lorlatinib, has shown severe teratogenicity in mice, leading to malformations and abortion (Pfizer report). However, in humans, two clinical cases of pregnant patients treated with alectinib resulted in normal childbirth and development [114,115]. During embryological development, ALK is present throughout the CNS, including in specific regions of the brain such as the thalamus, mid-brain, olfactory bulb, and ganglia [98,110]. The expression of ALK, together with LTK, in the hippocampus and amygdala is associated with memory and anxiety. Interestingly, ALK KO mice show enhanced cognitive performance and reduced anxiety, while LTK KO mice do not show any significant changes [96]. In Drosophila, ALK inhibition has been shown to enhance olfactory-connected learning [116].
However, ALK KO mice consume greater doses of alcohol, and the mechanism behind this phenotype appears to be within the nucleus accumbens, where ALK regulates excitatory synapses from post-synaptic neurons. The loss of ALK enhances the excitatory transmission in nucleus accumbens neurons [113]. ALK also regulates the behavioral response to cocaine [112]. ALK has been associated with other psychiatric pathologies, including schizophrenia, but additional research is needed [117]. Hopefully, further research on ALK-Augα and LTK-Augβ signaling pathways will help identify the precise roles of these proteins in various neurological and psychiatric pathologies.

8. Reproductive System

The expression of ALK in both the testes and ovaries is well established in the scientific literature [98,110]. Young male patients who are prescribed ALK inhibitors such as crizotinib and ceritinib may experience endocrine side effects, which can lead to symptoms resembling hypogonadism and severely reduced testosterone levels. Studies have shown that this is likely due to CNS-mediated mechanisms, as FSH and LH levels in these patients are low. Fortunately, these side effects are reversible upon drug discontinuation and can be treated with testosterone supplements [118,119]. Interestingly, mice with ALK knockouts (KOs), either from exon 1 deletion or kinase deletion, have exhibited delayed breeding, which seems to be associated with puberty delay. Prepubertal ALK KO mice also show mild disorganization in seminiferous tubules. Testosterone levels, hypothalamic GnRH neuronal levels, and Sertoli cell numbers are low at the prepubertal stage, but they normalize once mice enter puberty [119]. Puberty delay might be beneficial for patients with precox puberty, which is becoming a growing concern [120]. Additionally, treating WT mice with crizotinib (at a high 20 mg/kg concentration) has been shown to decrease adult testosterone levels [119]. Whether this observation is physiologic remains to be elucidated with additional research efforts involving the role of Augs in reproduction.

9. Conclusions and Perspectives

As demonstrated by various studies, the signaling pathways involving ALK-Augα and LTK-Augβ play a significant role in several biological systems (Figure 3). Thus, it is crucial for clinicians prescribing ALK inhibitors to consider the roles that these pathways play in normal human physiology. Additionally, understanding the mechanisms of action through structural and biophysical studies has helped in the development of monoclonal antibodies that may be repurposed to treat specific types of cancer and pathological pain [20]. Brain-penetrating TKIs also hold potential for modifying psychiatric and neurological disorders [96], metabolic syndrome [69], and precocious puberty [119]. Moreover, based on the ophthalmological phenotypes described, analogs of the AD could potentially be used as eye drops [23,102]. When key mechanistic insights are discovered, therapeutic development becomes trivial. Therefore, it is essential for the academic community to continue its efforts in clarifying the roles of Augs in the mentioned phenotypes and potentially uncovering new physiological roles for these signaling cascades.

Author Contributions

L.K., conceptualization, investigation, writing, and editing. A.P., reviewing and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data was created.

Acknowledgments

We express our gratitude to Joseph Schlessinger (Yale University) for support and encouragement in implementing the idea of this review article. We are appreciative of Mansoor Ahmed (Yale University) for exceptional and insightful discussions on the subject, demonstrating the potential for a successful future as a Principal Investigator. Special thanks are due to Martina Glavan (Yale University) for her generous assistance in creating graphical illustrations through BioRender.com (access date 27th September 2023).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zhang, H.; Pao, L.I.; Zhou, A.; Brace, A.D.; Halenbeck, R.; Hsu, A.W.; Bray, T.L.; Hestir, K.; Bosch, E.; Lee, E.; et al. Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome. Proc. Natl. Acad. Sci. USA 2014, 111, 15741–15745. [Google Scholar] [CrossRef]
  2. Palomo, V.; Nozal, V.; Rojas-Prats, E.; Gil, C.; Martinez, A. Protein kinase inhibitors for amyotrophic lateral sclerosis therapy. Br. J. Pharmacol. 2021, 178, 1316–1335. [Google Scholar] [CrossRef] [PubMed]
  3. Abdelsayed, M.; Kort, E.J.; Jovinge, S.; Mercola, M. Repurposing drugs to treat cardiovascular disease in the era of precision medicine. Nat. Rev. Cardiol. 2022, 19, 751–764. [Google Scholar] [CrossRef] [PubMed]
  4. Duggan, B.M.; Marko, D.M.; Muzaffar, R.; Chan, D.Y.; Schertzer, J.D. Kinase inhibitors for cancer alter metabolism, blood glucose, and insulin. J. Endocrinol. 2023, 256, e220212. [Google Scholar] [CrossRef]
  5. Roskoski, R. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol. Res. 2019, 144, 19–50. [Google Scholar] [CrossRef] [PubMed]
  6. Shepard, H.M.; Phillips, G.L.; Thanos, C.D.; Feldmann, M. Developments in therapy with monoclonal antibodies and related proteins. Clin. Med. 2017, 17, 220–232. [Google Scholar] [CrossRef] [PubMed]
  7. Gharwan, H.; Groninger, H. Kinase inhibitors and monoclonal antibodies in oncology: Clinical implications. Nat. Rev. Clin. Oncol. 2016, 13, 209–227. [Google Scholar] [CrossRef] [PubMed]
  8. Fauvel, B.; Yasri, A. Antibodies directed against receptor tyrosine kinases. mAbs 2014, 6, 838–851. [Google Scholar] [CrossRef]
  9. Maliartchouk, S.; Debeir, T.; Beglova, N.; Cuello, A.C.; Gehring, K.; Saragovi, H.U. Genuine Monovalent Ligands of TrkA Nerve Growth Factor Receptors Reveal a Novel Pharmacological Mechanism of Action. J. Biol. Chem. 2000, 275, 9946–9956. [Google Scholar] [CrossRef]
  10. Lampson, L.A. Monoclonal antibodies in neuro-oncology. mAbs 2011, 3, 153–160. [Google Scholar] [CrossRef]
  11. Moroder, L.; Musiol, H.J. Insulin—From its Discovery to the Industrial Synthesis of Modern Insulin Analogues. Angew. Chem. Int. Ed. 2017, 56, 10656–10669. [Google Scholar] [CrossRef] [PubMed]
  12. Lemmon, M.A.; Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2010, 141, 1117–1134. [Google Scholar] [CrossRef] [PubMed]
  13. Schlessinger, J. Receptor tyrosine kinases: Legacy of the first two decades. Cold Spring Harb. Perspect. Biol. 2014, 6, a008912. [Google Scholar] [CrossRef] [PubMed]
  14. Ben-Neriah, Y.; Bauskin, A.R. Leukocytes express a novel gene encoding a putative transmembrane protein-kinase devoid of an extracellular domain. Nature 1988, 333, 672–676. [Google Scholar] [CrossRef] [PubMed]
  15. Morris, S.W.; Kirstein, M.N.; Valentine, M.B.; Dittmer, K.G.; Shapiro, D.N.; Saltman, D.L.; Look, A.T. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994, 263, 1281–1284. [Google Scholar] [CrossRef]
  16. Murray, P.B.; Lax, I.; Reshetnyak, A.; Ligon, G.F.; Lillquist, J.S.; Natoli, E.J.; Shi, X.; Folta-Stogniew, E.; Gunel, M.; Alvarado, D.; et al. Heparin is an activating ligand of the orphan receptor tyrosine kinase, ALK. Sci. Signal. 2015, 8, ra6. [Google Scholar] [CrossRef] [PubMed]
  17. Reshetnyak, A.V.; Murray, P.B.; Shi, X.; Mo, E.S.; Mohanty, J.; Tome, F.; Bai, H.; Gunel, M.; Lax, I.; Schlessinger, J. Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions. Proc. Natl. Acad. Sci. USA 2015, 112, 15862–15867. [Google Scholar] [CrossRef] [PubMed]
  18. Reshetnyak, A.V.; Rossi, P.; Myasnikov, A.G.; Sowaileh, M.; Mohanty, J.; Nourse, A.; Miller, D.J.; Lax, I.; Schlessinger, J.; Kalodimos, C.G. Mechanism for the activation of the anaplastic lymphoma kinase receptor. Nature 2021, 600, 153–157. [Google Scholar] [CrossRef]
  19. De Munck, S.; Provost, M.; Kurikawa, M.; Omori, I.; Mukohyama, J.; Felix, J.; Bloch, Y.; Abdel-Wahab, O.; Bazan, J.F.; Yoshimi, A.; et al. Structural basis of cytokine-mediated activation of ALK family receptors. Nature 2021, 600, 143–147. [Google Scholar] [CrossRef]
  20. Li, T.; Stayrook, S.E.; Tsutsui, Y.; Zhang, J.; Wang, Y.; Li, H.; Proffitt, A.; Krimmer, S.G.; Ahmed, M.; Belliveau, O.; et al. Structural basis for ligand reception by anaplastic lymphoma kinase. Nature 2021, 600, 148–152. [Google Scholar] [CrossRef]
  21. Lorén, C.E.; Englund, C.; Grabbe, C.; Hallberg, B.; Hunter, T.; Palmer, R.H. A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster. EMBO Rep. 2003, 4, 781–786. [Google Scholar] [CrossRef]
  22. Reiner, D.J.; Ailion, M.; Thomas, J.H.; Meyer, B.J.C. elegans Anaplastic Lymphoma Kinase Ortholog SCD-2 Controls Dauer Formation by Modulating TGF-β Signaling. Curr. Biol. 2008, 18, 1101–1109. [Google Scholar] [CrossRef]
  23. Fadeev, A.; Mendoza-Garcia, P.; Irion, U.; Guan, J.; Pfeifer, K.; Wiessner, S.; Serluca, F.; Singh, A.P.; Nüsslein-Volhard, C.; Palmer, R.H. ALKALs are in vivo ligands for ALK family receptor tyrosine kinases in the neural crest and derived cells. Proc. Natl. Acad. Sci. USA 2018, 115, E630–E638. [Google Scholar] [CrossRef]
  24. Degoutin, J.; Brunet-de Carvalho, N.; Cifuentes-Diaz, C.; Vigny, M. ALK (Anaplastic Lymphoma Kinase) expression in DRG neurons and its involvement in neuron-Schwann cells interaction. Eur. J. Neurosci. 2009, 29, 275–286. [Google Scholar] [CrossRef]
  25. Huang, H.; Gont, A.; Kee, L.; Dries, R.; Pfeifer, K.; Sharma, B.; Debruyne, D.N.; Harlow, M.; Sengupta, S.; Guan, J.; et al. Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration. Cell Rep. 2021, 36, 109363. [Google Scholar] [CrossRef]
  26. Englund, C.; Lorén, C.E.; Grabbe, C.; Varshney, G.K.; Deleuil, F.; Hallberg, B.; Palmer, R.H. Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion. Nature 2003, 425, 512–516. [Google Scholar] [CrossRef]
  27. Lee, H.H.; Norris, A.; Weiss, J.B.; Frasch, M. Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers. Nature 2003, 425, 507–512. [Google Scholar] [CrossRef]
  28. Ishihara, T.; Iino, Y.; Mohri, A.; Mori, I.; Gengyo-Ando, K.; Mitani, S.; Katsura, I. HEN-1, a Secretory Protein with an LDL Receptor Motif, Regulates Sensory Integration and Learning in Caenorhabditis elegans. Cell 2002, 109, 639–649. [Google Scholar] [CrossRef]
  29. Wang, Z.; Dornburg, A.; Wang, J.; Mo, E.S.; Lopez-Giraldez, F.; Townsend, J.P. Evolutionary analyses guide selection of model systems to investigate proto-oncogene function in ALK and LTK. bioRxiv 2019. [CrossRef]
  30. Guan, J.; Umapathy, G.; Yamazaki, Y.; Wolfstetter, G.; Mendoza, P.; Pfeifer, K.; Mohammed, A.; Hugosson, F.; Zhang, H.; Hsu, A.W.; et al. FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase. Davis R, editor. eLife 2015, 4, e09811. [Google Scholar] [CrossRef]
  31. Reshetnyak, A.V.; Mohanty, J.; Tomé, F.; Puleo, D.E.; Plotnikov, A.N.; Ahmed, M.; Kaur, N.; Poliakov, A.; Cinnaiyan, A.M.; Lax, I.; et al. Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α). Proc. Natl. Acad. Sci. USA 2018, 115, 8340–8345. [Google Scholar] [CrossRef] [PubMed]
  32. Hallberg, B.; Palmer, R.H. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat. Rev. Cancer 2013, 13, 685–700. [Google Scholar] [CrossRef] [PubMed]
  33. Duyster, J.; Bai, R.Y.; Morris, S.W. Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 2001, 20, 5623–5637. [Google Scholar] [CrossRef] [PubMed]
  34. Mano, H. Non-solid oncogenes in solid tumors: EML4–ALK fusion genes in lung cancer. Cancer Sci. 2008, 99, 2349–2355. [Google Scholar] [CrossRef] [PubMed]
  35. Hallberg, B.; Palmer, R.H. The role of the ALK receptor in cancer biology. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2016, 27 (Suppl. S3), iii4–iii15. [Google Scholar] [CrossRef] [PubMed]
  36. Lovly, C.M.; Heuckmann, J.M.; de Stanchina, E.; Chen, H.; Thomas, R.K.; Liang, C.; Pao, W. Insights into ALK-Driven Cancers Revealed through Development of Novel ALK Tyrosine Kinase Inhibitors. Cancer Res. 2011, 71, 4920–4931. [Google Scholar] [CrossRef] [PubMed]
  37. Lin, J.J.; Riely, G.J.; Shaw, A.T. Targeting ALK: Precision Medicine Takes on Drug Resistance. Cancer Discov. 2017, 7, 137–155. [Google Scholar] [CrossRef] [PubMed]
  38. Murugan, A.K.; Xing, M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res. 2011, 71, 4403–4411. [Google Scholar] [CrossRef]
  39. Guan, J.; Wolfstetter, G.; Siaw, J.; Chand, D.; Hugosson, F.; Palmer, R.H.; Hallberg, B. Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent. Oncotarget 2016, 8, 11566–11578. [Google Scholar] [CrossRef]
  40. Ono, S.; Saito, T.; Terui, K.; Yoshida, H.; Enomoto, H. Generation of conditional ALK F1174L mutant mouse models for the study of neuroblastoma pathogenesis. Genesis 2019, 57, e23323. [Google Scholar] [CrossRef]
  41. Cazes, A.; Lopez-Delisle, L.; Tsarovina, K.; Pierre-Eugène, C.; De Preter, K.; Peuchmaur, M.; Nicolas, A.; Provost, C.; Louis-Brennetot, C.; Daveau, R.; et al. Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma. Oncotarget 2014, 5, 2688–2702. [Google Scholar] [CrossRef] [PubMed]
  42. Berry, T.; Luther, W.; Bhatnagar, N.; Jamin, Y.; Poon, E.; Sanda, T.; Pei, D.; Sharma, B.; Vetharoy, W.R.; Hallsworth, A.; et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell 2012, 22, 117–130. [Google Scholar] [CrossRef] [PubMed]
  43. Heukamp, L.C.; Thor, T.; Schramm, A.; De Preter, K.; Kumps, C.; De Wilde, B.; Odersky, A.; Peifer, M.; Lindner, S.; Spruessel, A.; et al. Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci. Transl. Med. 2012, 4, 141ra91. [Google Scholar] [CrossRef] [PubMed]
  44. Zhu, S.; Lee, J.S.; Guo, F.; Shin, J.; Perez-Atayde, A.R.; Kutok, J.L.; Rodig, S.J.; Neuberg, D.S.; Helman, D.; Feng, H.; et al. Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell 2012, 21, 362–373. [Google Scholar] [CrossRef] [PubMed]
  45. Schönherr, C.; Ruuth, K.; Kamaraj, S.; Wang, C.L.; Yang, H.L.; Combaret, V.; Djos, A.; Martinsson, T.; Christensen, J.G.; Palmer, R.H.; et al. Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells. Oncogene 2012, 31, 5193–5200. [Google Scholar] [CrossRef] [PubMed]
  46. Hasan, M.K.; Nafady, A.; Takatori, A.; Kishida, S.; Ohira, M.; Suenaga, Y.; Hossain, S.; Akter, J.; Ogura, A.; Nakamura, Y.; et al. ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma. Sci. Rep. 2013, 3, 3450. [Google Scholar] [CrossRef] [PubMed]
  47. Borenäs, M.; Umapathy, G.; Lai, W.Y.; Lind, D.E.; Witek, B.; Guan, J.; Mendoza-Garcia, P.; Masudi, T.; Claeys, A.; Chuang, T.-P.; et al. ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation. EMBO J. 2021, 40, e105784. [Google Scholar] [CrossRef]
  48. Mossé, Y.P.; Lim, M.S.; Voss, S.D.; Wilner, K.; Ruffner, K.; Laliberte, J.; Rolland, D.; Balis, F.M.; Maris, J.M.; Weigel, B.J.; et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: A Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013, 14, 472–480. [Google Scholar] [CrossRef]
  49. Javanmardi, N.; Fransson, S.; Djos, A.; Umapathy, G.; Östensson, M.; Milosevic, J.; Borenäs, M.; Hallberg, B.; Kogner, P.; Martinsson, T.; et al. Analysis of ALK, MYCN, and the ALK ligand ALKAL2 (FAM150B/AUGα) in neuroblastoma patient samples with chromosome arm 2p rearrangements. Genes Chromosomes Cancer 2020, 59, 50–57. [Google Scholar] [CrossRef]
  50. Guan, J.; Hallberg, B.; Palmer, R.H. Chromosome Imbalances in Neuroblastoma-Recent Molecular Insight into Chromosome 1p-deletion, 2p-gain, and 11q-deletion Identifies New Friends and Foes for the Future. Cancers 2021, 13, 5897. [Google Scholar] [CrossRef]
  51. Schleiermacher, G.; Javanmardi, N.; Bernard, V.; Leroy, Q.; Cappo, J.; Rio Frio, T.; Pierron, G.; Lapouble, E.; Combaret, V.; Speleman, F.; et al. Emergence of new ALK mutations at relapse of neuroblastoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2014, 32, 2727–2734. [Google Scholar] [CrossRef]
  52. Treis, D.; Umapathy, G.; Fransson, S.; Guan, J.; Mendoza-García, P.; Siaw, J.T.; Wessman, S.; Gordon Murkes, L.; Stenman, J.J.E.; Djos, A.; et al. Sustained Response to Entrectinib in an Infant With a Germline ALKAL2 Variant and Refractory Metastatic Neuroblastoma With Chromosomal 2p Gain and Anaplastic Lymphoma Kinase and Tropomyosin Receptor Kinase Activation. JCO Precis. Oncol. 2022, 6, e2100271. [Google Scholar] [CrossRef] [PubMed]
  53. Brodeur, G.M. Spontaneous regression of neuroblastoma. Cell Tissue Res. 2018, 372, 277–286. [Google Scholar] [CrossRef] [PubMed]
  54. Patel, J.S.; Pearson, J.; Willatt, L.; Andrews, T.; Beach, R.; Green, A. Germline duplication of chromosome 2p and neuroblastoma. J. Med. Genet. 1997, 34, 949–951. [Google Scholar] [CrossRef] [PubMed]
  55. Dowa, Y.; Yamamoto, T.; Abe, Y.; Kobayashi, M.; Hoshino, R.; Tanaka, K.; Aida, N.; Take, H.; Kato, K.; Tanaka, Y.; et al. Congenital Neuroblastoma in a Patient With Partial Trisomy of 2p. J. Pediatr. Hematol. Oncol. 2006, 28, 379. [Google Scholar] [CrossRef] [PubMed]
  56. Nagano, H.; Kano, Y.; Kobuchi, S.; Kajitani, T. A case of partial 2p trisomy with neuroblastoma. Jpn. J. Hum. Genet. 1980, 25, 39–45. [Google Scholar] [CrossRef]
  57. Lopez, G.; Conkrite, K.L.; Doepner, M.; Rathi, K.S.; Modi, A.; Vaksman, Z.; Farra, L.M.; Hyson, E.; Noureddine, M.; Wei, J.S.; et al. Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma. Genome Res. 2020, 30, 1228–1242. [Google Scholar] [CrossRef]
  58. Siaw, J.T.; Javanmardi, N.; Van den Eynden, J.; Lind, D.E.; Fransson, S.; Martinez-Monleon, A.; Djos, A.; Sjöberg, R.-M.; Östensson, M.; Carén, H.; et al. 11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma. Cell Rep. 2020, 32, 108171. [Google Scholar] [CrossRef]
  59. van Groningen, T.; Koster, J.; Valentijn, L.J.; Zwijnenburg, D.A.; Akogul, N.; Hasselt, N.E.; Broekmans, M.; Haneveld, F.; Nowakowska, N.E.; Bras, J.; et al. Neuroblastoma is composed of two super-enhancer-associated differentiation states. Nat. Genet. 2017, 49, 1261–1266. [Google Scholar] [CrossRef]
  60. Peterson, S.; Bogenmann, E. The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. Oncogene 2004, 23, 213–225. [Google Scholar] [CrossRef]
  61. Siaw, J.T.; Gabre, J.L.; Uçkun, E.; Vigny, M.; Zhang, W.; Van den Eynden, J.; Hallberg, B.; Palmer, R.H.; Guan, J. Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells. Cancers 2021, 13, 1909. [Google Scholar] [CrossRef] [PubMed]
  62. Lopez-Delisle, L.; Pierre-Eugène, C.; Louis-Brennetot, C.; Surdez, D.; Raynal, V.; Baulande, S.; Boeva, V.; Grossetête-Lalami, S.; Combaret, V.; Peuchmaur, M.; et al. Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis. Oncogene 2018, 37, 1417–1429. [Google Scholar] [CrossRef] [PubMed]
  63. Lambertz, I.; Kumps, C.; Claeys, S.; Lindner, S.; Beckers, A.; Janssens, E.; Carter, D.R.; Cazes, A.; Cheung, B.B.; De Mariano, M.; et al. Upregulation of MAPK Negative Feedback Regulators and RET in Mutant ALK Neuroblastoma: Implications for Targeted Treatment. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2015, 21, 3327–3339. [Google Scholar] [CrossRef] [PubMed]
  64. Chen, S.; Wang, B.; Fu, X.; Liang, Y.; Chai, X.; Ye, Z.; Li, R.; He, Y.; Kong, G.; Lian, J.; et al. ALKAL1 gene silencing prevents colorectal cancer progression via suppressing Sonic Hedgehog (SHH) signaling pathway. J. Cancer 2021, 12, 150–162. [Google Scholar] [CrossRef] [PubMed]
  65. Mazzeschi, M.; Sgarzi, M.; Romaniello, D.; Gelfo, V.; Cavallo, C.; Ambrosi, F.; Morselli, A.; Miano, C.; Laprovitera, N.; Girone, C.; et al. The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer. J. Exp. Clin. Cancer Res. 2022, 41, 113. [Google Scholar] [CrossRef] [PubMed]
  66. Guinney, J.; Dienstmann, R.; Wang, X.; de Reyniès, A.; Schlicker, A.; Soneson, C.; Marisa, L.; Roepman, P.; Nyamundanda, G.; Angelino, P.; et al. The Consensus Molecular Subtypes of Colorectal Cancer. Nat. Med. 2015, 21, 1350–1356. [Google Scholar] [CrossRef] [PubMed]
  67. Bilsland, J.G.; Wheeldon, A.; Mead, A.; Znamenskiy, P.; Almond, S.; Waters, K.A.; Thakur, M.; Beaumont, V.; Bonnert, T.P.; Heavens, R.; et al. Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 2008, 33, 685–700. [Google Scholar] [CrossRef] [PubMed]
  68. Orthofer, M.; Valsesia, A.; Mägi, R.; Wang, Q.P.; Kaczanowska, J.; Kozieradzki, I.; Leopoldi, A.; Cikes, D.; Zopf, L.M.; Tretiakov, E.O.; et al. Identification of ALK in Thinness. Cell 2020, 181, 1246–1262.e22. [Google Scholar] [CrossRef]
  69. Ahmed, M.; Kaur, N.; Cheng, Q.; Shanabrough, M.; Tretiakov, E.O.; Harkany, T.; Horvath, T.L.; Schlessinger, J. A hypothalamic pathway for Augmentor α-controlled body weight regulation. Proc. Natl. Acad. Sci. USA 2022, 119, e2200476119. [Google Scholar] [CrossRef]
  70. Berthoud, H.R.; Neuhuber, W.L. Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 2000, 85, 1–17. [Google Scholar] [CrossRef]
  71. Affleck, V.S.; Coote, J.H.; Pyner, S. The projection and synaptic organisation of NTS afferent connections with presympathetic neurons, GABA and nNOS neurons in the paraventricular nucleus of the hypothalamus. Neuroscience 2012, 219, 48–61. [Google Scholar] [CrossRef] [PubMed]
  72. Defaye, M.; Iftinca, M.C.; Gadotti, V.M.; Basso, L.; Abdullah, N.S.; Cuménal, M.; Agosti, F.; Hassan, A.; Flynn, R.; Martin, J.; et al. The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain. J. Clin. Investig. 2022, 132, e154317. [Google Scholar] [CrossRef] [PubMed]
  73. Reed, M.; Rosales, A.L.S.; Chioda, M.D.; Parker, L.; Devgan, G.; Kettle, J. Consensus Recommendations for Management and Counseling of Adverse Events Associated with Lorlatinib: A Guide for Healthcare Practitioners. Adv. Ther. 2020, 37, 3019–3030. [Google Scholar] [CrossRef] [PubMed]
  74. Goldsmith, K.C.; Park, J.R.; Kayser, K.; Malvar, J.; Chi, Y.Y.; Groshen, S.G.; Villablanca, J.G.; Krytska, K.; Lai, L.M.; Acharya, P.T.; et al. Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: Phase 1 trial results. Nat. Med. 2023, 29, 1092–1102. [Google Scholar] [CrossRef] [PubMed]
  75. Yao, S.; Wu, H.; Ding, J.-M.; Wang, Z.-X.; Ullah, T.; Dong, S.-S.; Chen, H.; Guo, Y. Transcriptome-wide association study identifies multiple genes associated with childhood body mass index. Int. J. Obes. 2021, 45, 1105–1113. [Google Scholar] [CrossRef] [PubMed]
  76. Cervantes-Madrid, D.; Szydzik, J.; Lind, D.E.; Borenäs, M.; Bemark, M.; Cui, J.; Palmer, R.H.; Hallberg, B. Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells. Sci. Rep. 2019, 9, 19353. [Google Scholar] [CrossRef] [PubMed]
  77. Marchand, S. Mechanisms Challenges of the Pain Phenomenon. Front. Pain Res. 2021, 1, 574370. [Google Scholar] [CrossRef]
  78. Basbaum, A.I.; Bautista, D.M.; Scherrer, G.; Julius, D. Cellular and Molecular Mechanisms of Pain. Cell 2009, 139, 267–284. [Google Scholar] [CrossRef]
  79. Ji, R.R.; Strichartz, G. Cell Signaling and the Genesis of Neuropathic Pain. Sci. STKE 2004, 2004, re14. [Google Scholar] [CrossRef]
  80. Woolf, C.J.; Max, M.B. Mechanism-based Pain Diagnosis: Issues for Analgesic Drug Development. Anesthesiology 2001, 95, 241–249. [Google Scholar] [CrossRef]
  81. Modi, A.D.; Parekh, A.; Pancholi, Y.N. Evaluating pain behaviours: Widely used mechanical and thermal methods in rodents. Behav. Brain Res. 2023, 446, 114417. [Google Scholar] [CrossRef] [PubMed]
  82. Ji, R.R.; Gereau, R.W.; Malcangio, M.; Strichartz, G.R. MAP kinase and pain. Brain Res. Rev. 2009, 60, 135–148. [Google Scholar] [CrossRef] [PubMed]
  83. Stamboulian, S.; Choi, J.S.; Ahn, H.S.; Chang, Y.W.; Tyrrell, L.; Black, J.A.; Waxman, S.G.; Dib-Hajj, S.D. ERK1/2 Mitogen-Activated Protein Kinase Phosphorylates Sodium Channel Nav1.7 and Alters Its Gating Properties. 7 and Alters Its Gating Properties. J. Neurosci. 2010, 30, 1637–1647. [Google Scholar] [CrossRef]
  84. Devor, M. Unexplained peculiarities of the dorsal root ganglion. Pain 1999, 82, S27–S35. [Google Scholar] [CrossRef]
  85. Pleasure, S.J.; Page, C.; Lee, V.M. Pure, postmitotic, polarized human neurons derived from NTera 2 cells provide a system for expressing exogenous proteins in terminally differentiated neurons. J. Neurosci. 1992, 12, 1802–1815. [Google Scholar] [CrossRef] [PubMed]
  86. Kersten, C.; Cameron, M.G. Cetuximab alleviates neuropathic pain despite tumour progression. BMJ Case Rep. 2012, 2012, bcr1220115374. [Google Scholar] [CrossRef] [PubMed]
  87. Kersten, C.; Cameron, M.G.; Laird, B.; Mjåland, S. Epidermal growth factor receptor-inhibition (EGFR-I) in the treatment of neuropathic pain. Br. J. Anaesth. 2015, 115, 761–767. [Google Scholar] [CrossRef] [PubMed]
  88. Khan, M.; Lin, J.; Liao, G.; Tian, Y.; Liang, Y.; Li, R.; Liu, M.; Yuan, Y. ALK Inhibitors in the Treatment of ALK Positive, NSCLC. Front. Oncol. 2019, 8, 557. [Google Scholar] [CrossRef]
  89. Hochberg, M.C. Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies. Osteoarthr. Cartil. 2015, 23, S18–S21. [Google Scholar] [CrossRef]
  90. Mahato, A.K.; Sidorova, Y.A. Glial cell line-derived neurotrophic factors (GFLs) and small molecules targeting RET receptor for the treatment of pain and Parkinson’s disease. Cell Tissue Res. 2020, 382, 147–160. [Google Scholar] [CrossRef]
  91. Andres, C.; Hasenauer, J.; Ahn, H.S.; Joseph, E.K.; Isensee, J.; Theis, F.J.; Allgöwer, F.; Levine, J.D.; Dib-Hajj, S.D.; Waxman, S.G.; et al. Wound-healing growth factor, basic FGF, induces Erk1/2-dependent mechanical hyperalgesia. Pain 2013, 154, 2216–2226. [Google Scholar] [CrossRef] [PubMed]
  92. Lázár, B.A.; Jancsó, G.; Sántha, P. Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth. Int. J. Mol. Sci. 2020, 21, 2507. [Google Scholar] [CrossRef] [PubMed]
  93. Wang, Y.; Barker, K.; Shi, S.; Diaz, M.; Mo, B.; Gutstein, H.B. Blockade of PDGFR-β activation eliminates morphine analgesic tolerance. Nat. Med. 2012, 18, 385–387. [Google Scholar] [CrossRef] [PubMed]
  94. Sun, Y.G.; Gracias, N.G.; Drobish, J.K.; Vasko, M.R.; Gereau, R.W.; Chen, Z.F. The c-kit signaling pathway is involved in the development of persistent pain. Pain 2009, 144, 178–186. [Google Scholar] [CrossRef] [PubMed]
  95. Stover, J.D.; Farhang, N.; Berrett, K.C.; Gertz, J.; Lawrence, B.; Bowles, R.D. CRISPR Epigenome Editing of AKAP150 in DRG Neurons Abolishes Degenerative IVD-Induced Neuronal Activation. Mol. Ther. 2017, 25, 2014–2027. [Google Scholar] [CrossRef] [PubMed]
  96. Weiss, J.B.; Xue, C.; Benice, T.; Xue, L.; Morris, S.W.; Raber, J. Anaplastic lymphoma kinase and leukocyte tyrosine kinase: Functions and genetic interactions in learning, memory and adult neurogenesis. Pharmacol. Biochem. Behav. 2012, 100, 566–574. [Google Scholar] [CrossRef] [PubMed]
  97. Chelala, E.; Hoyek, S.; Arej, N.; Kattan, J.; Kourie, H.R.; Baakliny, J.; Antoun, J. Ocular and orbital side effects of ALK inhibitors: A review article. Future Oncol. 2019, 15, 1939–1945. [Google Scholar] [CrossRef] [PubMed]
  98. Vernersson, E.; Khoo, N.K.S.; Henriksson, M.L.; Roos, G.; Palmer, R.H.; Hallberg, B. Characterization of the expression of the ALK receptor tyrosine kinase in mice. Gene Expr. Patterns 2006, 6, 448–461. [Google Scholar] [CrossRef]
  99. Belmonte, C.; Acosta, M.C.; Merayo-Lloves, J.; Gallar, J. What Causes Eye Pain? Curr. Ophthalmol. Rep. 2015, 3, 111–121. [Google Scholar] [CrossRef]
  100. Bazigou, E.; Apitz, H.; Johansson, J.; Lorén, C.E.; Hirst, E.M.A.; Chen, P.-L.; Palmer, R.H.; Salecker, I. Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila. Cell 2007, 128, 961–975. [Google Scholar] [CrossRef]
  101. Martinsson, T.; Eriksson, T.; Abrahamsson, J.; Caren, H.; Hansson, M.; Kogner, P.; Kamaraj, S.; Schönherr, C.; Weinmar, J.; Ruuth, K.; et al. Appearance of the Novel Activating F1174S ALK Mutation in Neuroblastoma Correlates with Aggressive Tumor Progression and Unresponsiveness to Therapy. Cancer Res. 2011, 71, 98–105. [Google Scholar] [CrossRef] [PubMed]
  102. Mo, E.S.; Cheng, Q.; Reshetnyak, A.V.; Schlessinger, J.; Nicoli, S. Alk and Ltk ligands are essential for iridophore development in zebrafish mediated by the receptor tyrosine kinase Ltk. Proc. Natl. Acad. Sci. USA 2017, 114, 12027–12032. [Google Scholar] [CrossRef]
  103. Fadeev, A.; Krauss, J.; Singh, A.P.; Nüsslein-Volhard, C. Zebrafish Leucocyte tyrosine kinase controls iridophore establishment, proliferation and survival. Pigment Cell Melanoma Res. 2016, 29, 284–296. [Google Scholar] [CrossRef] [PubMed]
  104. Kelsh, R.N.; Brand, M.; Jiang, Y.J.; Heisenberg, C.P.; Lin, S.; Haffter, P.; Odenthal, J.; Mullins, M.C.; van Eeden, F.J.; Furutani-Seiki, M.; et al. Zebrafish pigmentation mutations and the processes of neural crest development. Development 1996, 123, 369–389. [Google Scholar] [CrossRef] [PubMed]
  105. Singh, A.P.; Schach, U.; Nüsslein-Volhard, C. Proliferation, dispersal and patterned aggregation of iridophores in the skin prefigure striped colouration of zebrafish. Nat. Cell Biol. 2014, 16, 604–611. [Google Scholar] [CrossRef] [PubMed]
  106. Selleck, M.A.J.; Bronner-Fraser, M. Origins of the avian neural crest: The role of neural plate-epidermal interactions. Development 1995, 121, 525–538. [Google Scholar] [CrossRef]
  107. Kabangu, M.; Cecil, R.; Strohl, L.; Timoshevskaya, N.; Smith, J.J.; Voss, S.R. Leukocyte Tyrosine Kinase (Ltk) Is the Mendelian Determinant of the Axolotl Melanoid Color Variant. Genes 2023, 14, 904. [Google Scholar] [CrossRef]
  108. Coblentz, J.; Logan, P.T.; Dias, A.B.T.; Esposito, E.; Mansure, J.J.; Burnier, M.N. Expression of anaplastic lymphoma kinase in uveal melanoma. Investig. Ophthalmol. Vis. Sci. 2017, 58, 3955. [Google Scholar] [CrossRef]
  109. Surriga, O.; Rajasekhar, V.K.; Ambrosini, G.; Dogan, Y.; Huang, R.; Schwartz, G.K. Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model. Mol. Cancer Ther. 2013, 12, 2817–2826. [Google Scholar] [CrossRef]
  110. Iwahara, T.; Fujimoto, J.; Wen, D.; Cupples, R.; Bucay, N.; Arakawa, T.; Mori, S.; Ratzkin, B.; Yamamoto, T. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 1997, 14, 439–449. [Google Scholar] [CrossRef]
  111. Rohrbough, J.; Kent, K.S.; Broadie, K.; Weiss, J.B. Jelly Belly Trans-Synaptic Signaling to Anaplastic Lymphoma Kinase Regulates Neurotransmission Strength and Synapse Architecture. Dev. Neurobiol. 2013, 73, 189–208. [Google Scholar] [CrossRef] [PubMed]
  112. Lasek, A.W.; Gesch, J.; Giorgetti, F.; Kharazia, V.; Heberlein, U. Alk is a transcriptional target of LMO4 and ERα that promotes cocaine sensitization and reward. J. Neurosci. Off. J. Soc. Neurosci. 2011, 31, 14134–14141. [Google Scholar] [CrossRef] [PubMed]
  113. Mangieri, R.A.; Maier, E.Y.; Buske, T.R.; Lasek, A.W.; Morrisett, R.A. Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell. Front. Pharmacol. 2017, 8, 533. [Google Scholar] [CrossRef] [PubMed]
  114. De Smedt, F.; Dessy, F.; Carestia, L.; Baldin, P.; Nana, F.A.; Clapuyt, P.; Boon, V.; Amant, F.; Gziri, M.M. A pregnant patient with ALK-positive non-small cell lung cancer treated with alectinib: A case report and review of the literature. Oncol. Lett. 2023, 25, 54. [Google Scholar] [CrossRef]
  115. Scarfone, G.; Fumagalli, M.; Imbimbo, M.; Ceruti, T.; Cribiù, F.M.; Di Loreto, E.; D’Incalci, M.; Facchin, F.; Fontana, C.; Garassino, M.C.; et al. First Case Report of Pregnancy on Alectinib in a Woman With Metastatic ALK-Rearranged Lung Cancer: A Case Report. J. Thorac. Oncol. 2021, 16, 873–877. [Google Scholar] [CrossRef] [PubMed]
  116. Gouzi, J.Y.; Bouraimi, M.; Roussou, I.G.; Moressis, A.; Skoulakis, E.M.C. The Drosophila Receptor Tyrosine Kinase Alk Constrains Long-Term Memory Formation. J. Neurosci. 2018, 38, 7701–7712. [Google Scholar] [CrossRef] [PubMed]
  117. Kunugi, H.; Hashimoto, R.; Okada, T.; Hori, H.; Nakabayashi, T.; Baba, A.; Kudo, K.; Omori, M.; Takahashi, S.; Tsukue, R.; et al. Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population. J. Neural Transm. 2006, 113, 1569–1573. [Google Scholar] [CrossRef] [PubMed]
  118. Weickhardt, A.J.; Rothman, M.S.; Salian-Mehta, S.; Kiseljak-Vassiliades, K.; Oton, A.B.; Doebele, R.C.; Wierman, M.E.; Camidge, D.R. Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer 2012, 118, 5302–5309. [Google Scholar] [CrossRef]
  119. Witek, B.; El Wakil, A.; Nord, C.; Ahlgren, U.; Eriksson, M.; Vernersson-Lindahl, E.; Helland, Å.; Alexeyev, O.A.; Hallberg, B.; Palmer, R.H. Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism. PLoS ONE 2015, 10, e0123542. [Google Scholar] [CrossRef]
  120. Fuqua, J.S. Treatment and Outcomes of Precocious Puberty: An Update. J. Clin. Endocrinol. Metab. 2013, 98, 2198–2207. [Google Scholar] [CrossRef]
Biomolecules 13 01490 g001
Figure 1. ALK and LTK receptors and species-specific respective ligands representative through evolution.
Figure 1. ALK and LTK receptors and species-specific respective ligands representative through evolution.
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Figure 2. Receptor–ligand interactions. (a) LTK and Augα proposed mechanism of interaction by Savvides research group; (b) ALK and Augα proposed mechanism of interaction by Schlessinger, Klein, and Kalodimos research groups.
Figure 2. Receptor–ligand interactions. (a) LTK and Augα proposed mechanism of interaction by Savvides research group; (b) ALK and Augα proposed mechanism of interaction by Schlessinger, Klein, and Kalodimos research groups.
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Figure 3. Organ-specific roles of ALK and Augα signaling axis.
Figure 3. Organ-specific roles of ALK and Augα signaling axis.
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Table 1. Comparison of structural studies on ALK family receptors and Augα.
Table 1. Comparison of structural studies on ALK family receptors and Augα.
Research GroupTruncationsEGF-like
Domain
Importance		Size Exclusion
Chromatography
(Receptor:Ligand)		Method UsedStructural
Complex
(Receptor:Ligand)
ALKAugα
SavvidesTG-EGFL
(648–1038)		AD
(78–152)		YesNo shift (1:1)X-ray
crystallography		1:2
Klein, SchlessingerTG-EGFL
(678–1030)		AD
(71–152)		Yes(fusion protein)X-ray
crystallography		2:2
Kalodimos, SchlessingerTG-EGFL
(673–1025)		Full size
+ C66Y		YesShift (2:2)cryoEM
NMR		2:2
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Katic, L.; Priscan, A. Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review. Biomolecules 2023, 13, 1490. https://doi.org/10.3390/biom13101490

AMA Style

Katic L, Priscan A. Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review. Biomolecules. 2023; 13(10):1490. https://doi.org/10.3390/biom13101490

Chicago/Turabian Style

Katic, Luka, and Anamarija Priscan. 2023. "Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review" Biomolecules 13, no. 10: 1490. https://doi.org/10.3390/biom13101490

APA Style

Katic, L., & Priscan, A. (2023). Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review. Biomolecules, 13(10), 1490. https://doi.org/10.3390/biom13101490

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