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Cells
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Receptor Tyrosine Kinases
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Receptor Tyrosine Kinases

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 November 2013) | Viewed by 109138

Special Issue Editor

Dr. Sassan Hafizi

E-Mail Website
Guest Editor
School of Pharmacy and Biomedical Sciences, University of Portsmouth, St. Michael's Building, White Swan Road, Portsmouth PO1 2DT, UK
Interests: epigenetics; focal adhesion proteins; receptor tyrosine kinases; cell signalling; vitamin K; cancer; myelin; multiple sclerosis; brain tumours; renal carcinoma; cytoskeleton; cell migration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the earliest discoveries of growth factors in the 1950s and of transmembrane receptors for these factors that possess protein tyrosine kinase activity in the 1970s, the body of knowledge on receptor tyrosine kinases (RTKs) has increased appreciably. The uniqueness in structure and ligand-binding specificities of the ectodomain of RTKs determines their subclassification, and today we know of the existence of around 20 different RTK classes, with a number and diversity of ligands that is ever increasing. Despite this diversity, RTKs continue to together represent a major group of molecules that play important roles in both health and disease. Normal RTK function is associated with development, cell and tissue growth and differentiation and cell-cell and cell-matrix interaction, whereas RTK overactivity and/or overexpression is a common feature in many cancers. However, novel aspects to RTK structure and function are increasingly becoming apparent as more research is being done. Amongst these include ligand-dependent and -independent mechanisms of activation, alternative and unexpected receptor clustering patterns, spatial and temporal control of RTK signalling, intracellular RTK functions, RTKs as entry gateways for pathogens, and as highly attractive candidates in target-specific cancer therapy. The aim with this Special Issue of Cells is to offer an Open Access collection of scholarly reviews on the forefront of research on RTKs that covers all of the above aspects and more. We hope to provide a stimulating resource that will inform the student and the academic on the breadth and diversity of RTK biology. This is a field that is sure to maintain a high level of interest and research activity from both academic and industrial sectors with interests in science and medicine well into the future.

Dr. Sassan Hafizi
Guest Editor

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Keywords

  • receptor tyrosine kinases
  • growth factor
  • signal transduction
  • phosphorylation
  • spatial and temporal signalling
  • tyrosine kinase domain
  • transmembrane domain
  • RTK class
  • dimerisation
  • docking protein
  • development
  • differentiation
  • cancer
  • monoclonal antibodies
  • small molecule inhibitors
  • anti-cancer drug resistance

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Published Papers (9 papers)

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Editorial

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143 KiB  
Editorial
Receptor Tyrosine Kinases — Expanding Horizons
by Sassan Hafizi
Cells 2014, 3(2), 657-659; https://doi.org/10.3390/cells3020657 - 20 Jun 2014
Viewed by 4930
Abstract
This Special Issue of Cells on receptor tyrosine kinases (RTKs) is a timely and unique assemblage of scholarly insights into topics that have relatively recently entered the spotlight in relation to this class of molecules. The review by Julien et al. [1] is [...] Read more.
This Special Issue of Cells on receptor tyrosine kinases (RTKs) is a timely and unique assemblage of scholarly insights into topics that have relatively recently entered the spotlight in relation to this class of molecules. The review by Julien et al. [1] is an overview of the knowledge on how gangliosides, constituting certain membrane microdomains, may interact with and regulate RTK activation and downstream signalling. Similarly, the review by Banning et al. [2] focuses on the influence of another type of membrane microdomain, namely that containing flotillins, on regulation of RTK signalling and its relevance to cancer. Both of these reviews provide novel insights into mechanisms of transmembrane receptor signalling that rely on the constitution of the microdomains the RTKs reside in, and how their modification may affect receptor clustering, activation and translocation. Thus, knowledge about such microdomains and their interactions with RTKs can provide new information on common regulation pathways starting at the membrane level, which could have implications for novel therapeutic angles in, e.g., cancer. [...] Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)

Research

Jump to: Editorial, Review

1278 KiB  
Article
Endosome-to-Plasma Membrane Recycling of VEGFR2 Receptor Tyrosine Kinase Regulates Endothelial Function and Blood Vessel Formation
by Helen M. Jopling, Adam F. Odell, Caroline Pellet-Many, Antony M. Latham, Paul Frankel, Asipu Sivaprasadarao, John H. Walker, Ian C. Zachary and Sreenivasan Ponnambalam
Cells 2014, 3(2), 363-385; https://doi.org/10.3390/cells3020363 - 29 Apr 2014
Cited by 53 | Viewed by 12342
Abstract
Rab GTPases are implicated in endosome-to-plasma membrane recycling, but how such membrane traffic regulators control vascular endothelial growth factor receptor 2 (VEGFR2/KDR) dynamics and function are not well understood. Here, we evaluated two different recycling Rab GTPases, Rab4a and Rab11a, in regulating endothelial [...] Read more.
Rab GTPases are implicated in endosome-to-plasma membrane recycling, but how such membrane traffic regulators control vascular endothelial growth factor receptor 2 (VEGFR2/KDR) dynamics and function are not well understood. Here, we evaluated two different recycling Rab GTPases, Rab4a and Rab11a, in regulating endothelial VEGFR2 trafficking and signalling with implications for endothelial cell migration, proliferation and angiogenesis. In primary endothelial cells, VEGFR2 displays co-localisation with Rab4a, but not Rab11a GTPase, on early endosomes. Expression of a guanosine diphosphate (GDP)-bound Rab4a S22N mutant caused increased VEGFR2 accumulation in endosomes. TfR and VEGFR2 exhibited differences in endosome-to-plasma membrane recycling in the presence of chloroquine. Depletion of Rab4a, but not Rab11a, levels stimulated VEGF-A-dependent intracellular signalling. However, depletion of either Rab4a or Rab11a levels inhibited VEGF-A-stimulated endothelial cell migration. Interestingly, depletion of Rab4a levels stimulated VEGF-A-regulated endothelial cell proliferation. Rab4a and Rab11a were also both required for endothelial tubulogenesis. Evaluation of a transgenic zebrafish model showed that both Rab4 and Rab11a are functionally required for blood vessel formation and animal viability. Rab-dependent endosome-to-plasma membrane recycling of VEGFR2 is important for intracellular signalling, cell migration and proliferation during angiogenesis. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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Review

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1568 KiB  
Review
Systems Analysis of Drug-Induced Receptor Tyrosine Kinase Reprogramming Following Targeted Mono- and Combination Anti-Cancer Therapy
by Alexey Goltsov, Yusuf Deeni, Hilal S. Khalil, Tero Soininen, Stylianos Kyriakidis, Huizhong Hu, Simon P. Langdon, David J. Harrison and James Bown
Cells 2014, 3(2), 563-591; https://doi.org/10.3390/cells3020563 - 10 Jun 2014
Cited by 27 | Viewed by 12223
Abstract
The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the [...] Read more.
The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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297 KiB  
Review
Mechanisms of Activation of Receptor Tyrosine Kinases: Monomers or Dimers
by Ichiro N. Maruyama
Cells 2014, 3(2), 304-330; https://doi.org/10.3390/cells3020304 - 22 Apr 2014
Cited by 153 | Viewed by 21791
Abstract
Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except [...] Read more.
Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except for the insulin receptor (IR) family, are activated by ligand-induced dimerization of the receptors. An increasing number of diverse studies, however, indicate that RTKs, previously thought to exist as monomers, are present as pre-formed, yet inactive, dimers prior to ligand binding. The non-covalently associated dimeric structures are reminiscent of those of the IR family, which has a disulfide-linked dimeric structure. Furthermore, recent progress in structural studies has provided insight into the underpinnings of conformational changes during the activation of RTKs. In this review, I discuss two mutually exclusive models for the mechanisms of activation of the epidermal growth factor receptor, the neurotrophin receptor and IR families, based on these new insights. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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398 KiB  
Review
Role of Receptor Tyrosine Kinases and Their Ligands in Glioblastoma
by Estefanía Carrasco-García, Miguel Saceda and Isabel Martínez-Lacaci
Cells 2014, 3(2), 199-235; https://doi.org/10.3390/cells3020199 - 4 Apr 2014
Cited by 68 | Viewed by 13379
Abstract
Glioblastoma multiforme is the most frequent, aggressive and fatal type of brain tumor. Glioblastomas are characterized by their infiltrating nature, high proliferation rate and resistance to chemotherapy and radiation. Recently, oncologic therapy experienced a rapid evolution towards “targeted therapy,” which is the employment [...] Read more.
Glioblastoma multiforme is the most frequent, aggressive and fatal type of brain tumor. Glioblastomas are characterized by their infiltrating nature, high proliferation rate and resistance to chemotherapy and radiation. Recently, oncologic therapy experienced a rapid evolution towards “targeted therapy,” which is the employment of drugs directed against particular targets that play essential roles in proliferation, survival and invasiveness of cancer cells. A number of molecules involved in signal transduction pathways are used as molecular targets for the treatment of various tumors. In fact, inhibitors of these molecules have already entered the clinic or are undergoing clinical trials. Cellular receptors are clear examples of such targets and in the case of glioblastoma multiforme, some of these receptors and their ligands have become relevant. In this review, the importance of glioblastoma multiforme in signaling pathways initiated by extracellular tyrosine kinase receptors such as EGFR, PDGFR and IGF-1R will be discussed. We will describe their ligands, family members, structure, activation mechanism, downstream molecules, as well as the interaction among these pathways. Lastly, we will provide an up-to-date review of the current targeted therapies in cancer, in particular glioblastoma that employ inhibitors of these pathways and their benefits. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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502 KiB  
Review
Flotillins in Receptor Tyrosine Kinase Signaling and Cancer
by Antje Banning, Nina Kurrle, Melanie Meister and Ritva Tikkanen
Cells 2014, 3(1), 129-149; https://doi.org/10.3390/cells3010129 - 19 Feb 2014
Cited by 53 | Viewed by 10428
Abstract
Flotillins are highly conserved proteins that localize into specific cholesterol rich microdomains in cellular membranes. They have been shown to be associated with, for example, various signaling pathways, cell adhesion, membrane trafficking and axonal growth. Recent findings have revealed that flotillins are frequently [...] Read more.
Flotillins are highly conserved proteins that localize into specific cholesterol rich microdomains in cellular membranes. They have been shown to be associated with, for example, various signaling pathways, cell adhesion, membrane trafficking and axonal growth. Recent findings have revealed that flotillins are frequently overexpressed in various types of human cancers. We here review the suggested functions of flotillins during receptor tyrosine kinase signaling and in cancer. Although flotillins have been implicated as putative cancer therapy targets, we here show that great caution is required since flotillin ablation may result in effects that increase instead of decrease the activity of specific signaling pathways. On the other hand, as flotillin overexpression appears to be related with metastasis formation in certain cancers, we also discuss the implications of these findings for future therapy aspects. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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Graphical abstract

793 KiB  
Review
Unlocking Doors without Keys: Activation of Src by Truncated C-terminal Intracellular Receptor Tyrosine Kinases Lacking Tyrosine Kinase Activity
by Belén Mezquita, Pau Mezquita, Montserrat Pau, Jovita Mezquita and Cristóbal Mezquita
Cells 2014, 3(1), 92-111; https://doi.org/10.3390/cells3010092 - 14 Feb 2014
Cited by 13 | Viewed by 12058
Abstract
One of the best examples of the renaissance of Src as an open door to cancer has been the demonstration that just five min of Src activation is sufficient for transformation and also for induction and maintenance of cancer stem cells [1]. Many [...] Read more.
One of the best examples of the renaissance of Src as an open door to cancer has been the demonstration that just five min of Src activation is sufficient for transformation and also for induction and maintenance of cancer stem cells [1]. Many tyrosine kinase receptors, through the binding of their ligands, become the keys that unlock the structure of Src and activate its oncogenic transduction pathways. Furthermore, intracellular isoforms of these receptors, devoid of any tyrosine kinase activity, still retain the ability to unlock Src. This has been shown with a truncated isoform of KIT (tr-KIT) and a truncated isoform of VEGFR-1 (i21-VEGFR-1), which are intracellular and require no ligand binding, but are nonetheless able to activate Src and induce cell migration and invasion of cancer cells. Expression of the i21-VEGFR-1 is upregulated by the Notch signaling pathway and repressed by miR-200c and retinoic acid in breast cancer cells. Both Notch inhibitors and retinoic acid have been proposed as potential therapies for invasive breast cancer. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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Graphical abstract

529 KiB  
Review
When Good Turns Bad: Regulation of Invasion and Metastasis by ErbB2 Receptor Tyrosine Kinase
by Ditte Marie Brix, Knut Kristoffer Bundgaard Clemmensen and Tuula Kallunki
Cells 2014, 3(1), 53-78; https://doi.org/10.3390/cells3010053 - 27 Jan 2014
Cited by 24 | Viewed by 10636
Abstract
Overexpression and activation of ErbB2 receptor tyrosine kinase in breast cancer is strongly linked to an aggressive disease with high potential for invasion and metastasis. In addition to inducing very aggressive, metastatic cancer, ErbB2 activation mediates processes such as increased cancer cell proliferation [...] Read more.
Overexpression and activation of ErbB2 receptor tyrosine kinase in breast cancer is strongly linked to an aggressive disease with high potential for invasion and metastasis. In addition to inducing very aggressive, metastatic cancer, ErbB2 activation mediates processes such as increased cancer cell proliferation and survival and is needed for normal physiological activities, such as heart function and development of the nervous system. How does ErbB2 activation make cancer cells invasive and when? Comprehensive understanding of the cellular mechanisms leading to ErbB2-induced malignant processes is necessary for answering these questions. Here we present current knowledge about the invasion-promoting function of ErbB2 and the mechanisms involved in it. Obtaining detailed information about the “bad” behavior of ErbB2 can facilitate development of novel treatments against ErbB2-positive cancers. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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Graphical abstract

488 KiB  
Review
How Do Gangliosides Regulate RTKs Signaling?
by Sylvain Julien, Marie Bobowski, Agata Steenackers, Xuefen Le Bourhis and Philippe Delannoy
Cells 2013, 2(4), 751-767; https://doi.org/10.3390/cells2040751 - 6 Dec 2013
Cited by 88 | Viewed by 10214
Abstract
Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are located on the outer leaflet of the plasma membrane in glycolipid-enriched microdomains, where they interact with molecules of signal transduction pathways including receptors tyrosine kinases (RTKs). The role of gangliosides in the [...] Read more.
Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are located on the outer leaflet of the plasma membrane in glycolipid-enriched microdomains, where they interact with molecules of signal transduction pathways including receptors tyrosine kinases (RTKs). The role of gangliosides in the regulation of signal transduction has been reported in many cases and in a large number of cell types. In this review, we summarize the current knowledge on the biosynthesis of gangliosides and the mechanism by which they regulate RTKs signaling. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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