Professor Razin is a world-leading scientist in the field of mast cell biology. His first major contribution was over 30 years ago, when he developed a cultured mouse bone marrow-derived mast cell model. This system changed mast cell research and is still one of the main tools for studying mast cell function. Around 10 years ago, his group presented a key advancement in the field when they reported a previously unknown signaling pathway directly involved in gene regulation.

The main focus of the present proposal is further exploration of this pathway, which involves the ubiquitously expressed Hint1, a repressor of both USF2 and MITF transcriptional activity via its tight association to these proteins. The interaction between USF2 or MITF and Hint1 is reduced upon physiological stimulation in several cell types, as a result of the synthesis of Ap4A, acting as a 2nd messenger as described by Prof. Razin’s team. He also demonstrated that following physiological stimulation in these cell types, 207 serine phosphorylated lysyl tRNA synthetase (LysRS) associates with either of these transcription factors and forms a multi-complex with Hint. 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 2nd messenger binds specifically to Hint1, 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-Hint1, the enzyme Ap4A hydrolase catalyzes the excess intracellular Ap4A. This research has been described in eleven publications and is summarized in this animation http://tinyurl.com/o5hd2m7. 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. This paper was reported in the news of the day section of the Science Daily News (http://tinyurl.com/lun4yp8) and was featured in the News Beyond Our Pages section of the JACI (http://tinyurl.com/qdnnej4). Recent papers of his own and others have served to demonstrate the importance of this pathway in diseases such as non-small cell carcinoma  and melanoma and in HIV-1 infection.

Professor Razin now felt that it was time to expand this research to in vivo systems, which led to his pioneering work on 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 often precedes heart 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 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 a decrease in function and severe pathological growth of heart muscle. His findings also revealed a link between Erbin and the Hint1-MITF-LysRS-Ap4A pathway since Erbin expression is regulated by MITF in mice and human hearts.

Prof Razin’s work has contributed significantly to understanding the role of PIAS3, the main cellular inhibitor of STAT3, in activated mast cells. MITF and STAT3 are key players in the regulation of mast cell growth and function. Prof. Razin’s team has elucidated the role of PIAS3 in the regulation of transcriptional activity and the molecular mechanism involved. Based almost solely on Prof. Razin’s research, five Norwegian mathematicians presented a 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. Recently his team explored the potential involvement of STAT3 in mitochondrial ATP production and in exocytosis of immunologically activated mast cells  and the involvement of MITF and pyruvate dehydrogenase in this process. 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.

Over the years, Prof Razin has published his research in top peer-reviewed journals such as Immunity, The Journal of Clinical Investigation, Molecular Cell Biology, Molecular Cell, The Journal of Allergy and Clinical Immunology and The Proceedings of the National Academy of Science. His research is supported by top competitive grants available to Israeli scientists. He has supervised many graduate students some of whom are now faculty members in academic institutions in Israel.

Current Research Interests

Project: Inflammatory signalling pathways in mast cells

Selected Publications

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.

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.

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.

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. (This paper was described in the News Beyond Our Pages section of The Journal of Allergy and Clinical Immunology http://www.jacionline.org/article/S0091-6749(13)00186-3/fulltext#sec4).

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.

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. (This paper was highlighted in the In This Issue section of the journal http://www.pnas.org/content/111/16/5755.full).

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. J Allergy Clin Immunol, 2014. 134: p 460-469 e410. (This paper was featured on the cover of the respective http://www.jacionline.org/article/S0091-6749(14)00901-4/abstract).

Sharkia, I., T. Hadad Erlich, N. Landolina, M. Assayag, A. Motzik, I. Rachmin, G. Kay, Z. Porat, S. Tshori, N. Berkman, F. Levi-Schaffer, and E. Razin, Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor. J Allergy Clin Immunol, 2017. 140: p. 204-214.

Motzik, A., E. Amir, T. Erlich, J. Wang, B.G. Kim, J.M. Han, J.H. Kim, H. Nechushtan, M. Guo, E. Razin, and S. Tshori, Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in human melanoma cells. Oncogene, 2017. 36:  p. 4732-4738 (in press).

Boulos, S., M.C. Park, M. Zeibak, S.Y. Foo, Y.K. Jeon, Y.T. Kim, A. Motzik, S. Tshori, T. Hamburger, S. Kim, H. Nechushtan, and E. Razin, Serine 207 phosphorylated Lysyl-tRNA synthetase predicts disease-free survival of non-small-cell lung carcinoma. Oncotarget. 2017 (in press).

Laboratory Staff

Karen Or
Research Fellow
mickor@nus.edu.sg

Saravanan Vivekanandan
Research Fellow
micsav@nus.edu.sg

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