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A Special Issue Celebrating the Career of Prof. Dr. Greg Lemke: Multiple Roles of the TAM Signaling Pathway in Physiological Systems

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 15592

Special Issue Editor

Prof. Dr. Tal Burstyn-Cohen

E-Mail Website
Guest Editor
Development Biology and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem 91904, Israel
Interests: Protein S; PROS1; TAM signaling; homeostatic regulation; developmental biology; cancer biology

Special Issue Information

Dear Colleagues,

Since their cloning in 1991, the TAM receptors, comprising of Tyro3, Axl and Mertk have proven to govern many physiological aspects in health and in disease. Their function is necessary for maintaining a healthy homeostasis in various tissues, including the nervous, vascular, visual, bone and immune systems. This Special Issue celebrates the scientific career of Dr. Greg Lemke, on the occasion of his retirement. Greg's research has propelled our knowledge and shaped the current understanding on the complex biology of TAM signaling.

Their role in health notwithstanding, the TAM receptors as well as their secreted ligands GAS6 and Protein S (PROS1) are also emerging players in numerous maladies. The ramifications of TAM signaling are featured by their ubiquitous expression in different cell types and tissues, and by their interactions with additional signaling molecules such as phosphatidylserine and non-TAM membrane receptors.

This Special Issue aims to provide a unique and up-to-date collection of selected contributions on advances in understanding the multiple roles of TAM signaling in different physiological systems.

Prof. Dr. Tal Burstyn-Cohen
Guest Editor

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Keywords

  • TAM receptors
  • TAM signaling
  • GAS6
  • Protein S
  • physiological systems
  • phagocytosis
  • tissue homeostasis
  • TAM inhibitors

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Published Papers (7 papers)

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Research

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17 pages, 7581 KiB  
Article
Gas6 and Protein S Ligands Cooperate to Regulate MerTK Rhythmic Activity Required for Circadian Retinal Phagocytosis
by Célia Parinot, Jonathan Chatagnon, Quentin Rieu, Solène Roux, Dorine Néel, Florian Hamieh and Emeline F. Nandrot
Int. J. Mol. Sci. 2024, 25(12), 6630; https://doi.org/10.3390/ijms25126630 - 16 Jun 2024
Viewed by 1507
Abstract
Among the myriad of existing tyrosine kinase receptors, the TAM family—abbreviated from Tyro3, Axl, and Mer tyrosine kinase (MerTK)—has been extensively studied with an outstanding contribution from the team of Prof. Greg Lemke. MerTK activity is implicated in a wide variety of functions [...] Read more.
Among the myriad of existing tyrosine kinase receptors, the TAM family—abbreviated from Tyro3, Axl, and Mer tyrosine kinase (MerTK)—has been extensively studied with an outstanding contribution from the team of Prof. Greg Lemke. MerTK activity is implicated in a wide variety of functions involving the elimination of apoptotic cells and has recently been linked to cancers, auto-immune diseases, and atherosclerosis/stroke. In the retina, MerTK is required for the circadian phagocytosis of oxidized photoreceptor outer segments by the retinal-pigment epithelial cells, a function crucial for the long-term maintenance of vision. We previously showed that MerTK ligands carry the opposite role in vitro, with Gas6 inhibiting the internalization of photoreceptor outer segments while Protein S acts conversely. Using site-directed mutagenesis and ligand-stimulated phagocytosis assays on transfected cells, we presently demonstrate, for the first time, that Gas6 and Protein S recognize different amino acids on MerTK Ig-like domains. In addition, MerTK’s function in retinal-pigment epithelial cells is rhythmic and might thus rely on the respective stoichiometry of both ligands at different times of the day. Accordingly, we show that ligand bioavailability varies during the circadian cycle using RT-qPCR and immunoblots on retinal and retinal-pigment epithelial samples from control and beta5 integrin knockout mice where retinal phagocytosis is arrhythmic. Taken together, our results suggest that Gas6 and Protein S might both contribute to refine the acute regulation of MerTK in time for the daily phagocytic peak. Full article
(This article belongs to the Special Issue A Special Issue Celebrating the Career of Prof. Dr. Greg Lemke: Multiple Roles of the TAM Signaling Pathway in Physiological Systems)
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21 pages, 6069 KiB  
Article
Regulation of Mertk Surface Expression via ADAM17 and γ-Secretase Proteolytic Processing
by Kevin C. Lahey, Christopher Varsanyi, Ziren Wang, Ahmed Aquib, Varsha Gadiyar, Alcina A. Rodrigues, Rachael Pulica, Samuel Desind, Viralkumar Davra, David C. Calianese, Dongfang Liu, Jong-Hyun Cho, Sergei V. Kotenko, Mariana S. De Lorenzo and Raymond B. Birge
Int. J. Mol. Sci. 2024, 25(8), 4404; https://doi.org/10.3390/ijms25084404 - 17 Apr 2024
Cited by 2 | Viewed by 2735
Abstract
Mertk, a type I receptor tyrosine kinase and member of the TAM family of receptors, has important functions in promoting efferocytosis and resolving inflammation under physiological conditions. In recent years, Mertk has also been linked to pathophysiological roles in cancer, whereby, in several [...] Read more.
Mertk, a type I receptor tyrosine kinase and member of the TAM family of receptors, has important functions in promoting efferocytosis and resolving inflammation under physiological conditions. In recent years, Mertk has also been linked to pathophysiological roles in cancer, whereby, in several cancer types, including solid cancers and leukemia/lymphomas. Mertk contributes to oncogenic features of proliferation and cell survival as an oncogenic tyrosine kinase. In addition, Mertk expressed on macrophages, including tumor-associated macrophages, promotes immune evasion in cancer and is suggested to act akin to a myeloid checkpoint inhibitor that skews macrophages towards inhibitory phenotypes that suppress host T-cell anti-tumor immunity. In the present study, to better understand the post-translational regulation mechanisms controlling Mertk expression in monocytes/macrophages, we used a PMA-differentiated THP-1 cell model to interrogate the regulation of Mertk expression and developed a novel Mertk reporter cell line to study the intracellular trafficking of Mertk. We show that PMA treatment potently up-regulates Mertk as well as components of the ectodomain proteolytic processing platform ADAM17, whereas PMA differentially regulates the canonical Mertk ligands Gas6 and Pros1 (Gas6 is down-regulated and Pros1 is up-regulated). Under non-stimulated homeostatic conditions, Mertk in PMA-differentiated THP1 cells shows active constitutive proteolytic cleavage by the sequential activities of ADAM17 and the Presenilin/γ-secretase complex, indicating that Mertk is cleaved homeostatically by the combined sequential action of ADAM17 and γ-secretase, after which the cleaved intracellular fragment of Mertk is degraded in a proteasome-dependent mechanism. Using chimeric Flag-Mertk-EGFP-Myc reporter receptors, we confirm that inhibitors of γ-secretase and MG132, which inhibits the 26S proteasome, stabilize the intracellular fragment of Mertk without evidence of nuclear translocation. Finally, the treatment of cells with active γ-carboxylated Gas6, but not inactive Warfarin-treated non-γ-carboxylated Gas6, regulates a distinct proteolytic itinerary-involved receptor clearance and lysosomal proteolysis. Together, these results indicate that pleotropic and complex proteolytic activities regulate Mertk ectodomain cleavage as a homeostatic negative regulatory event to safeguard against the overactivation of Mertk. Full article
(This article belongs to the Special Issue A Special Issue Celebrating the Career of Prof. Dr. Greg Lemke: Multiple Roles of the TAM Signaling Pathway in Physiological Systems)
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22 pages, 1962 KiB  
Article
The Tolerogenic Influence of Dexamethasone on Dendritic Cells Is Accompanied by the Induction of Efferocytosis, Promoted by MERTK
by Vivien Li, Michele D. Binder and Trevor J. Kilpatrick
Int. J. Mol. Sci. 2023, 24(21), 15903; https://doi.org/10.3390/ijms242115903 - 2 Nov 2023
Cited by 2 | Viewed by 2352
Abstract
Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs [...] Read more.
Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs and upregulates MERTK expression. As MERTK can inhibit inflammation, we investigated whether dexamethasone’s tolerogenic effects are mediated via MERTK, potentially providing a novel therapeutic approach. Monocyte-derived DCs were treated with dexamethasone, and with and without MERTK ligands or MERTK inhibitors. Flow cytometry was used to assess effects of MERTK modulation on co-stimulatory molecule expression, efferocytosis, cytokine secretion and T cell proliferation. The influence on expression of Rab17, which coordinates the diversion of efferocytosed material away from cell surface presentation, was assessed. Dexamethasone-treated DCs had upregulated MERTK expression, decreased expression of co-stimulatory molecules, maturation and proliferation of co-cultured T cells and increased uptake of myelin debris. MERTK ligands did not potentiate these properties, whilst specific MERTK inhibition only reversed dexamethasone’s effect on myelin uptake. Cells undergoing efferocytosis had higher Rab17 expression. Dexamethasone-enhanced efferocytosis in DCs is MERTK-dependent and could exert its tolerogenic effects by increasing Rab17 expression to prevent the presentation of efferocytosed material on the cell surface to activate adaptive immune responses. Full article
(This article belongs to the Special Issue A Special Issue Celebrating the Career of Prof. Dr. Greg Lemke: Multiple Roles of the TAM Signaling Pathway in Physiological Systems)
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Review

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22 pages, 1431 KiB  
Review
MERTK Inhibition as a Targeted Novel Cancer Therapy
by K.M. Tanim, Alisha Holtzhausen, Aashis Thapa, Justus M. Huelse, Douglas K. Graham and H. Shelton Earp
Int. J. Mol. Sci. 2024, 25(14), 7660; https://doi.org/10.3390/ijms25147660 - 12 Jul 2024
Cited by 1 | Viewed by 2076
Abstract
In this issue honoring the contributions of Greg Lemke, the Earp and Graham lab teams discuss several threads in the discovery, action, signaling, and translational/clinical potential of MERTK, originally called c-mer, a member of the TYRO3, AXL, and MERTK (TAM) family of receptor [...] Read more.
In this issue honoring the contributions of Greg Lemke, the Earp and Graham lab teams discuss several threads in the discovery, action, signaling, and translational/clinical potential of MERTK, originally called c-mer, a member of the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases. The 30-year history of the TAM RTK family began slowly as all three members were orphan RTKs without known ligands and/or functions when discovered by three distinct alternate molecular cloning strategies in the pre-genome sequencing era. The pace of understanding their physiologic and pathophysiologic roles has accelerated over the last decade. The activation of ligands bridging externalized phosphatidylserine (PtdSer) has placed these RTKs in a myriad of processes including neurodevelopment, cancer, and autoimmunity. The field is ripe for further advancement and this article hopefully sets the stage for further understanding and therapeutic intervention. Our review will focus on progress made through the collaborations of the Earp and Graham labs over the past 30 years. Full article
(This article belongs to the Special Issue A Special Issue Celebrating the Career of Prof. Dr. Greg Lemke: Multiple Roles of the TAM Signaling Pathway in Physiological Systems)
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17 pages, 2189 KiB  
Review
In the Eyes of the Beholder—New Mertk Knockout Mouse and Re-Evaluation of Phagocytosis versus Anti-Inflammatory Functions of MERTK
by Sourav Ghosh, Silvia C. Finnemann, Douglas Vollrath and Carla V. Rothlin
Int. J. Mol. Sci. 2024, 25(10), 5299; https://doi.org/10.3390/ijms25105299 - 13 May 2024
Viewed by 1638
Abstract
Greg Lemke’s laboratory was one of the pioneers of research into the TAM family of receptor tyrosine kinases (RTKs). Not only was Tyro3 cloned in his laboratory, but his group also extensively studied mice knocked out for individual or various combinations of the [...] Read more.
Greg Lemke’s laboratory was one of the pioneers of research into the TAM family of receptor tyrosine kinases (RTKs). Not only was Tyro3 cloned in his laboratory, but his group also extensively studied mice knocked out for individual or various combinations of the TAM RTKs Tyro3, Axl, and Mertk. Here we primarily focus on one of the paralogs—MERTK. We provide a historical perspective on rodent models of loss of Mertk function and their association with retinal degeneration and blindness. We describe later studies employing mouse genetics and the generation of newer knockout models that point out incongruencies with the inference that loss of MERTK-dependent phagocytosis is sufficient for severe, early-onset photoreceptor degeneration in mice. This discussion is meant to raise awareness with regards to the limitations of the original Mertk knockout mouse model generated using 129 derived embryonic stem cells and carrying 129 derived alleles and the role of these alleles in modifying Mertk knockout phenotypes or even displaying Mertk-independent phenotypes. We also suggest molecular approaches that can further Greg Lemke’s scintillating legacy of dissecting the molecular functions of MERTK—a protein that has been described to function in phagocytosis as well as in the negative regulation of inflammation. Full article
(This article belongs to the Special Issue A Special Issue Celebrating the Career of Prof. Dr. Greg Lemke: Multiple Roles of the TAM Signaling Pathway in Physiological Systems)
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13 pages, 2134 KiB  
Review
The TAM Subfamily of Receptor Tyrosine Kinases: The Early Years
by Anne L. Prieto and Cary Lai
Int. J. Mol. Sci. 2024, 25(6), 3369; https://doi.org/10.3390/ijms25063369 - 16 Mar 2024
Viewed by 1249
Abstract
The TAMs are a subfamily of receptor tyrosine kinases (RTKs) comprised of three members, Tyro3, Axl and Mer. Evidence in support of the existence of this subfamily emerged from a screen for novel RTKs performed in the laboratory of Dr. Greg Lemke in [...] Read more.
The TAMs are a subfamily of receptor tyrosine kinases (RTKs) comprised of three members, Tyro3, Axl and Mer. Evidence in support of the existence of this subfamily emerged from a screen for novel RTKs performed in the laboratory of Dr. Greg Lemke in 1991. A PCR-based approach to selectively amplify tyrosine kinase-specific genes yielded 27 different tyrosine kinase genes, of which 13 were novel (the “Tyros”). Of these, Tyro3, 7 and 12 were more closely related to each other than to any other kinases and it was proposed that they constituted a novel subfamily of RTKs. Additional support for this hypothesis required determining the complete sequences for these receptor tyrosine kinases. By the end of 1991, full-length sequences for Tyro7 (Axl) revealed a unique extracellular domain organization that included two immunoglobulin-like domains and two fibronectin type III repeats. In 1994, the complete sequences for Tyro12 (Mer) and Tyro3 were shown to have an extracellular region domain structure similar to that of Axl. In 1995, Gas6 and Pros1 were reported as ligands for Tyro3 and Axl, setting the stage for functional studies. The Lemke lab and its many trainees have since played leading roles in elucidating the physiological relevance of the TAMs. Full article
(This article belongs to the Special Issue A Special Issue Celebrating the Career of Prof. Dr. Greg Lemke: Multiple Roles of the TAM Signaling Pathway in Physiological Systems)
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22 pages, 2395 KiB  
Review
The Role of TAM Receptors in Bone
by Janik Engelmann, Deniz Ragipoglu, Isabel Ben-Batalla and Sonja Loges
Int. J. Mol. Sci. 2024, 25(1), 233; https://doi.org/10.3390/ijms25010233 - 23 Dec 2023
Viewed by 3095
Abstract
The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver [...] Read more.
The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis by regulating osteoblastic bone formation and osteoclastic bone resorption. Therefore, TAM receptors emerge as new key players of the regulatory cytokine network of osteoblasts and osteoclasts and represent accessible targets for pharmacologic therapy for a broad set of different bone diseases, including primary and metastatic bone tumors, rheumatoid arthritis, or osteoporosis. Full article
(This article belongs to the Special Issue A Special Issue Celebrating the Career of Prof. Dr. Greg Lemke: Multiple Roles of the TAM Signaling Pathway in Physiological Systems)
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