Prof. Ehud Razin is considered to be one of the world-leading scientists in the field of mast cell biology. His first major contribution came more than thirty years ago, when he developed a cultured mouse bone marrow-derived mast cell model. The development of this system changed the history of mast cell research and is still one of the main tools for studying mast cell function.
Around ten years ago, based on intracellular signaling following physiological activation of mast cells as a model for other type of cells, his group presented a major advancement in the field when they discovered a new signaling pathway directly involved in gene regulation. This unique pathway involves the ubiquitously expressed Hint-1, which has been found to be a repressor of both USF2 and MITF transcriptional activity via its tight association to these proteins. The interaction between either USF2 or MITF and Hint-1 is reduced significantly upon physiological stimulation in variety of cell types. This dissociation occurs by the elevation of diadenosine tetraphosphate (Ap4A), acting as a second messenger as described by Prof. Razin’s team. His group’s data also demonstrated that following physiological stimulation in these cell types, 207 serine phosphorylated lysyl tRNA synthetase (LysRS) is associated with either one of these transcription factors and forms a multi-complex with Hint-1. This Erk-mediated phosphorylation is followed by a dramatic conformational change of the LysRS protein through the opening of its domain-domain interface. This enables it to not only be released from the multi- synthetase cytosolic complex, but also switches its function from catalysis of the formation of lysyl-tRNAs to the synthesis of Ap4A. This second messenger binds specifically to Hint-1, changes its confirmation and causes its dissociation from the transcription factors, which are now able to activate their target genes. In close proximity to these protein complexes of LysRS- transcription factors- Hint-1, the enzyme Ap4A hydrolase catalyzes the excess intracellular Ap4A. This research has been described in eleven publications and is summarized in this animation:
One of these publications describes his research performed in collaboration with a team from The Scripps Institute, Florida, which used a structural biology approach to confirm their earlier results as described above. The editors of Science Daily News described this paper in their news of the day
and a commentary on this paper appeared
in News Beyond Our Pages section of The Journal of Allergy and Clinical Immunology.
Prof. Razin now felt that it was time to expand this research into the more risky and challenging area of verifying his in vitro discoveries in in vivo systems. The first example of this can be seen in his pioneering work on the role played by MITF in cardiac hypertrophy. Cardiovascular disease remains the number one cause of death in the Western world, with heart failure representing the fastest-growing subclass over the past decade. The stage that precedes heart failure in a significant number of cardiovascular diseases is pathological hypertrophy — the growth of the heart muscle in an attempt to increase its output. Not all hypertrophy is pathological; for example, during pregnancy or high physical exertion, the muscle of the heart grows but myocardial function remains normal. However, when hypertrophy is excessive, prolonged and unbalanced, it becomes pathological, leading to heart failure and arrhythmias. Now for the first time, Prof. Razin’s team in collaboration with Prof Roger Foo from The National University of Singapore have revealed how a protein called Erbin acts as a brake against this excessive and pathological growth of heart muscle. They also demonstrated that damage to this protein leads to excess growth of heart muscle, a decrease in function, and severe pathological growth of heart muscle. His findings also revealed a previously unknown link between Erbin and the Hint1-MITF-LysRS-Ap4A pathway since his preliminary data clearly demonstrate that Erbin expression is regulated by MITF in mice and human hearts.
Prof Razin’s work has also contributed significantly to our understanding of the role played by PIAS3, the main cellular inhibitor of activated STAT3, in activated mast cells, and this is a growing and fascinating field. MITF and STAT3 play major roles in the regulation of growth and function in mast cells. Over the years, Prof. Razin’s team has provided the evidence regarding the key role of PIAS3 in the regulation of transcriptional activity, and on the molecular mechanism involved. These findings suggest that the known functions of these signaling molecules are merely the “tip of the iceberg”. Recently, based almost solely on more than a decade of Prof. Razin’s research, five Norwegian mathematicians presented a mathematical model describing the MITF-PIAS3-STAT3 signaling network, and concluded that this crosstalk between MITF and STAT3 via PIAS3 as described by Prof. Razin’s team offers a unique mechanistic explanation for MITF-PIAS3-STAT3 signaling in melanoma. Moreover, just recently his team explored the potential involvement of STAT3 in mitochondrial ATP production, and in exocytosis of immunologically activated mast cells. These results are of great importance since they provide the first direct evidence for an additional physiological function of STAT3 as a key regulator of mast cell exocytosis.
Lab membersDr. Gillian Kay
Tal Hadad Erlich
Dr. Suliman Boulos
Lee, Y.N., H. Nechushtan, N. Figov, and E. Razin, The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of MITF activity in FcRI-activated mast cells. Immunity, 2004. 20: p. 145-51. Link
Sonnenblick, A., C. Levy, and E. Razin, Interplay between MITF, PIAS3, and STAT3 in mast cells and melanocytes. Mol Cell Biol, 2004. 24: p. 10584-92. Link
Cohen-Saidon, C. and E. Razin, The involvement of Bcl-2 in mast cell apoptosis. Novartis Found Symp, 2005. 271: p. 191-5; discussion 195-9. Link
Lee, Y.N. and E. Razin, Nonconventional involvement of LysRS in the molecular mechanism of USF2 transcriptional activity in FcRI-activated mast cells. Mol Cell Biol, 2005. 25: p. 8904-12. Link
Sonnenblick, A., C. Levy, and E. Razin, Immunological trigger of mast cells by monomeric IgE: effect on microphthalmia transcription factor, STAT3 network of interactions. J Immunol, 2005. 175: p. 1450-5. Link
Cohen-Saidon, C., I. Carmi, A. Keren, and E. Razin, Antiapoptotic function of Bcl-2 in mast cells is dependent on its association with heat shock protein 90. Blood, 2006. 107: p. 1413-20. Link
Levy, C., Y.N. Lee, H. Nechushtan, O. Schueler-Furman, A. Sonnenblick, S. Hacohen, and E. Razin, Identifying a common molecular mechanism for inhibition of MITF and STAT3 by PIAS3. Blood, 2006. 107: p. 2839-45. Link
Tshori, S., D. Gilon, R. Beeri, H. Nechushtan, D. Kaluzhny, E. Pikarsky, and E. Razin, Transcription factor MITF regulates cardiac growth and hypertrophy. J Clin Invest, 2006. 116: p. 2673-81. Link
Yannay-Cohen, N. and E. Razin, Translation and transcription: the dual functionality of LysRS in mast cells. Mol Cells, 2006. 22: p. 127-32. Link
Carmi, I. and E. Razin, The role played by key transcription factors in activated mast cells. Immunol Rev, 2007. 217: p. 280-91. Link
Tshori, S., A. Sonnenblick, N. Yannay-Cohen, G. Kay, H. Nechushtan, and E. Razin, Microphthalmia transcription factor isoforms in mast cells and the heart. Mol Cell Biol, 2007. 27: p. 3911-9. Link
Carmi-Levy, I., N. Yannay-Cohen, G. Kay, E. Razin, and H. Nechushtan, Diadenosine tetraphosphate hydrolase is part of the transcriptional regulation network in immunologically activated mast cells. Mol Cell Biol, 2008. 28: p. 5777-84. Link
Nechushtan, H., S. Kim, G. Kay, and E. Razin, eds. The physiological role of lysyl tRNA synthetase in the immune system. Adv Immunol, ed. F.W. Alt. Vol. 103. 2009, Academic Press: Burlington. 1-27.
Yagil, Z., G. Kay, H. Nechushtan, and E. Razin, A specific epitope of protein inhibitor of activated STAT3 is responsible for the induction of apoptosis in rat transformed mast cells. J Immunol, 2009. 182: p. 2168-75. Link
Yannay-Cohen, N., I. Carmi-Levy, G. Kay, C.M. Yang, J.M. Han, D.M. Kemeny, S. Kim, H. Nechushtan, and E. Razin, LysRS serves as a key signaling molecule in the immune response by regulating gene expression. Mol Cell, 2009. 34: p. 603-11. Link
Yagil, Z., H. Nechushtan, G. Kay, C.M. Yang, D.M. Kemeny, and E. Razin, The enigma of the role of protein inhibitor of activated STAT3 (PIAS3) in the immune response. Trends Immunol, 2010. 31: p. 199-204. Link
Carmi-Levy, I., A. Motzik, Y. Ofir-Birin, Z. Yagil, C.M. Yang, D.M. Kemeny, J.M. Han, S. Kim, G. Kay, H. Nechushtan, R. Suzuki, J. Rivera, and E. Razin, Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap4A Pathway in Immunologically Activated Mast Cells. Mol Cell Biol, 2011. 31: p. 2111-21. Link
Yagil, Z., T. Hadad Erlich, Y. Ofir-Birin, S. Tshori, G. Kay, Z. Yekhtin, D.E. Fisher, C. Cheng, W.S. Wong, K. Hartmann, E. Razin, and H. Nechushtan, Transcription factor E3, a major regulator of mast cell-mediated allergic response. J Allergy Clin Immunol, 2012. 129: p. 1357-1366 e5. Link
Motzik, A., H. Nechushtan, S.Y. Foo, and E. Razin, Non-canonical roles of lysyl-tRNA synthetase in health and disease. Trends Mol Med, 2013. 19: p. 726-31. Link
Ofir-Birin, Y., P. Fang, S.P. Bennett, H.M. Zhang, J. Wang, I. Rachmin, R. Shapiro, J. Song, A. Dagan, J. Pozo, S. Kim, A.G. Marshall, P. Schimmel, X.L. Yang, H. Nechushtan, E. Razin, and M. Guo, Structural switch of lysyl-tRNA synthetase between translation and transcription. Mol Cell, 2013. 49: p. 30-42. Link
Tshori, S., E. Razin, and H. Nechushtan, Amino-Acyl tRNA synthetases generate dinucleotide polyphosphates as second messengers: Functional implications, in Top Curr Chem. 2013, Springer-Verlag: Berlin Heidelberg. Link
Rachmin, I., S. Tshori, Y. Smith, A. Oppenheim, S. Marchetto, G. Kay, R.S.-Y. Foo, N. Dagan, E. Golomb, D. Gilon, J.-P. Borg, and E. Razin, Erbin is a negative modulator of cardiac hypertrophy. Proceedings of the National Academy of Sciences, 2014. 111: p. 5902-5907. Link
Erlich, T.H., Z. Yagil, G. Kay, A. Peretz, H. Migalovich-Sheikhet, S. Tshori, H. Nechushtan, F. Levi-Schaffer, A. Saada, and E. Razin, Mitochondrial STAT3 plays a major role in IgE-antigen–mediated mast cell exocytosis. Journal of Allergy and Clinical Immunology, 2014. in press. Link