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Our lab is interested in understanding the molecular and cellular mechanisms that underlie tissue homeostasis in health and in disease. We investigate the role of TAM receptors and their agonists Protein S and Gas6 in development and throughout adulthood. We combine biochemical, cell-biological and genetically engineered mouse model approaches.
Tyro3, Axl, and MerTK comprise the TAM family of receptor tyrosine kinases. Together with their ligands Gas6 and Protein S (PROS1) TAM signaling plays a key role in maintaining a healthy balance in various physiological systems, including the endothelial, nervous, immune and reproductive systems.
Several human diseases are associated with the dysregulation of TAM signaling and its components, including blood hypercoagulation, inflammation, cancer, autoimmune disease and blindness.
We focus on the role of PROS1 as a TAM ligand in various physiological settings, to understand how PROS1-mediated TAM signaling is critical to homeostatic regulation. Specific projects in the lab focus on the developing and adult nervous system, the vascular system, in vision and in cancers.
Protein S mediated TAM signaling in development:
Using advanced transgenic mouse models, we have recently identified PROS1 expression in adult hippocampal neural stem cells (NSCs) (Zelentsova et al, Stem Cells, 2016). NSC proliferation and differentiation are essentially developmental processes that also occur postnatally, in the adult organism. PROS1 expression in adult NSC biology is multi-functional. We found that PROS1 functions as a stem cell quiescent factor, and maintains NSC quiescence through regulation of Notch. Later on, PROS1 is instructional for the birth of new neurons, in a process termed neurogenesis. Previously, we found that PROS1 is important for the development of blood vessels and for their healthy function in adulthood (Burstyn-Cohen et al, (2009) JCI). We are interested to learn more about the role of TAM signaling in the developing vasculature and the developing nervous system.
Protein S mediated TAM signaling in adult homeostasis:
In the eye: Mutations in MerTK lead to degeneration of photoreceptors, and consequent blindness in mice, rats and humans. However, the basic mechanism by which TAM signaling functions is not yet clear: what are the relevant ligand-receptor interactions? Which cells express them? In the lab, we aim to answer these questions in the eye, and to establish how PROS1 and TAM signaling is important for a healthy retina.
In cancer: TAMs were identified as proto-oncogenes, and their overexpression and hyper-activation is documented in many human cancers. However, which signals activate TAMs in cancers is not clearly understood. We study the role of PROS1-mediated TAM activation in various cancers, including in melanoma and the aggressive oral and lung carcinomas.
We recently identified the overexpression of PROS1 in Oral Squamous Cell Carcinoma (OSCC) from the tongue (Abboud-Jarrous et al, Oncotarget 2017). By performing in-vitro and in-vivo loss of function experiments, we found that PROS1 regulates OSCC tumorigenesis. Surprisingly, we also found that PROS1 regulates the expression of the TAM oncogenic receptor AXL, but does not affect TYRO3 or MER expression. Thus, although PROS1 probably does not activate AXL signaling through the classic ligand-receptor interaction, it can regulate AXL expression levels, which were previously shown signal in a ligand-independent manner.
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1. Abboud-Jarrous G, Priya S, Maimon A, Fischman S, Cohen-Elisha M, Czerninski R, and Tal Burstyn-Cohen. Protein S Drives Oral Squamous Cell Carcinoma Tumorigenicity through Regulation of AXL, (2017) Oncotarget. Jan 19, 2017. DOI: 10.18632/oncotarget.14753
2. Nassar M, Tabib Y, Capucha T, Mizraji G, Attal Z, Pevsner-Fischer M, Zilberman-Schapira G, Heyman O, Nussbaum G, Bercovier H, Wilensky A, Elinav E, Burstyn-Cohen T* and Hovav A-H*. GAS6 is a Key Homeostatic Regulator of Host-Commensal Interactions in the Oral Mucosa. PNAS Jan 2, 2017. *These Authors contributed equally to the work; Co-senior and co-corresponding authors.
3. Zelentsova K, Talmi Z, Abboud-Jarrous G, Sapir T, Capucha T, Nassar M. and Burstyn-Cohen, T. Protein S Regulates Neural Stem Cell Quiescence and Neurogenesis. (2016) Stem Cells, Nov 8, 2016. DOI: 10.1002/stem.2522
4. Carrera Silva EA, Chan PY, Joannas L, Errasti AE, Gagliani N, Bosurgi L, Jabbour M, Perry A, Smith-Chakmakova F, Mucida D, Cheroutre H, Burstyn-Cohen T, Leighton JA, Lemke G, Ghosh S and Rothlin CV. T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. Immunity. 2013; 39(1):160-170.
5. Burstyn-Cohen T, Lew ED, Traves PG, Burrola PG, Hash JC and Lemke G. Genetic dissection of TAM receptor-ligand interaction in retinal pigment epithelial cell phagocytosis. Neuron. 2012; 76(6):1123-1132.
6. Lemke G and Burstyn-Cohen T. TAM receptors and the clearance of apoptotic cells. Ann N Y Acad Sci. 2010; 1209:23-29.
7. Burstyn-Cohen T, Heeb MJ and Lemke G. Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J Clin Invest. 2009; 119(10):2942-2953.
8. Prasad D, Rothlin CV, Burrola P, Burstyn-Cohen T, Lu Q, Garcia de Frutos P and Lemke G. TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci. 2006; 33(1):96-108.
Collaborations and previous work:
9. Hagbi-Levi S, Grunin M, Elbaz-Hayoun S, Tal D, Obolensky A, Hanhart J, Banin E, Burstyn-Cohen T* and Chowers I*. Retinal Phenotype following Combined Deletion of the Chemokine Receptor CCR2 and the Chemokine CX3CL1 in Mice. Ophthalmic Res. 2016; 55(3):126-134.
10. Ben-Gedalya T, Moll L, Bejerano-Sagie M, Frere S, Cabral WA, Friedmann-Morvinski D, Slutsky I, Burstyn-Cohen T, Marini JC and Cohen E. Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction. Embo J. 2015; 34(22):2820-2839.
11. Capucha T, Mizraji G, Segev H, Blecher-Gonen R, Winter D, Khalaileh A, Tabib Y, Attal T, Nassar M, Zelentsova K, Kisos H, Zenke M, Sere K, Hieronymus T, Burstyn-Cohen T, Amit I, et al. Distinct Murine Mucosal Langerhans Cell Subsets Develop from Pre-dendritic Cells and Monocytes. Immunity. 2015; 43(2):369-381.
12. Sol A, Skvirsky Y, Nashef R, Zelentsova K, Burstyn-Cohen T, Blotnick E, Muhlrad A and Bachrach G. Actin enables the antimicrobial action of LL-37 peptide in the presence of microbial proteases. J Biol Chem. 2014; 289(33):22926-22941.
13. Jaouni T, Averbukh E, Burstyn-Cohen T, Grunin M, Banin E, Sharon D and Chowers I. Association of pattern dystrophy with an HTRA1 single-nucleotide polymorphism. Arch Ophthalmol. 2012; 130(8):987-991.
14. Grunin M, Burstyn-Cohen T, Hagbi-Levi S, Peled A and Chowers I. Chemokine receptor expression in peripheral blood monocytes from patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2012; 53(9):5292-5300.
15. Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Adame A, Pham HM, Holzenberger M, Kelly JW, Masliah E and Dillin A. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009; 139(6):1157-1169.
16. Stanojcic M*, Burstyn-Cohen T*, Nashi N, Lemke G and Sakic B. Disturbed distribution of proliferative brain cells during lupus-like disease. Brain Behav Immun. 2009; 23(7):1003-1013. *These Authors contributed equally to the work.
17. Kalcheim C and Burstyn-Cohen T. Early stages of neural crest ontogeny: formation and regulation of cell delamination. Int J Dev Biol. 2005; 49(2-3):105-116.
18. Burstyn-Cohen T, Stanleigh J, Sela-Donenfeld D and Kalcheim C. Canonical Wnt activity regulates trunk neural crest delamination linking BMP/noggin signaling with G1/S transition. Development. 2004; 131(21):5327-5339.
19. Burstyn-Cohen T and Kalcheim C. Association between the cell cycle and neural crest delamination through specific regulation of G1/S transition. Dev Cell. 2002; 3(3):383-395.
20. Tzarfati-Majar V, Burstyn-Cohen T and Klar A. F-spondin is a contact-repellent molecule for embryonic motor neurons. Proc Natl Acad Sci U S A. 2001; 98(8):4722-4727.
21. Feinstein Y, Borrell V, Garcia C, Burstyn-Cohen T, Tzarfaty V, Frumkin A, Nose A, Okamoto H, Higashijima S, Soriano E and Klar A. F-spondin and mindin: two structurally and functionally related genes expressed in the hippocampus that promote outgrowth of embryonic hippocampal neurons. Development. 1999; 126(16):3637-3648.
22. Burstyn-Cohen T, Tzarfaty V, Frumkin A, Feinstein Y, Stoeckli E and Klar A. F-Spondin is required for accurate pathfinding of commissural axons at the floor plate. Neuron. 1999; 23(2):233-246.
23. Debby-Brafman A, Burstyn-Cohen T, Klar A and Kalcheim C. F-Spondin, expressed in somite regions avoided by neural crest cells, mediates inhibition of distinct somite domains to neural crest migration. Neuron. 1999; 22(3):475-488.
24. Burstyn-Cohen T, Frumkin A, Xu YT, Scherer SS and Klar A. Accumulation of F-spondin in injured peripheral nerve promotes the outgrowth of sensory axons. J Neurosci. 1998; 18(21):8875-8885.
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We are located in the Ein Kerem Campus of the Hebrew University, Jerusalem.
Tal Burstyn-Cohen, PhD.
Feculty of Dental Medicine
Hebrew University – Hadassah
POB 12272, Jerusalem 91120, Israel
Tel (Office): +972-2-675-8582
Tel (Lab): +972-2-675-8585