Regulation of cell to cell communication in health and in cancer
In multicellular organisms, growth factors (GFs) and pro-inflammatory cytokines (PICs) control fundamental aspects of physiology, including cell proliferation, survival, migration, and tissue remodeling. Aberrant GFs/PICs signals are associated with diverse diseases including chronic inflammation and cancer implying that the strength and duration of these signals must be precisely regulated. An important mode of regulation involves negative feedback loops. The research in our laboratory focuses on studying an exceptional feedback antagonist termed Sef (IL-17RD) that is a tumor suppressor distinguished from other feedback antagonist via its capacity to modulate both growth-factor (GF) and pro-inflammatory cytokine (PIC) signaling. Current research topics: 1-Sef regulation of cross-talk between GF/PIC signaling during epithelial tissue formation; 2- Role of Sef as a link between cancer/inflammation; 3- Mechanisms by which Sef regulates PIC signaling; 4- Assessment of the potential of Sef for cancer therapy; 5- Regulation of Sef protein levels/activity. Collaborators: 1-Prof. Noam Adir, Faculty of Chemistry; 2- Prof. Petra Boukamp, German Cancer Research Center (DKFZ), Division of Genetics of Skin Carcinogenesis
1. Preger E., Ziv I., Shabtay A., Sher I., Tsand Michael, Dawid B. I., Altuvia Y. and Ron D. (2004) Alternative splicing generates a novel isoform of the human sef gene with altered subcellular localization and specificity. Proc. Natl. Acad. Sci. U.S.A. 101: 1229-1234.
2. Harduf, H., Halperin E., Reshef, R. and Ron D. (2005) Sef is synexpressed with FGFs during chick embryogenesis and its expression is differentially regulated by FGFs in the developing limb. Dev Dyn. 233: 301-12.
3. Sher, I., Zisman-Rozen, S., Eliahu, L., Whitelock, JM., Maas-Szabowski, N., Yamada, Y., Breitkreutz, D.,. Fusenig, NE., Arikawa-Hirasawa, E., Iozzo, RV., Bergman, R. and Ron D. (2006) Targeting perlecan in human keratinocytes reveals novel roles for perlecan in epidermis formation J Biol. Chem. 281(8):5178-87. Epub 2005 Nov 2. (Cited in the Faculty of 1000).
4. Ziv I., Fuchs Y., Preger E., Shabtay A., Harduf H., Zilpa T., Dym N and Ron D. (2006) The human Sef-a isoform utilizes different mechanisms to regulate FGFR signaling pathways and subsequent cell fate. J Biol Chem. 281:39225-39235
5. Zisman-Rozen, S., Fink, D., Ben-Izhak, O., Fuchs, Y., Brodski, A., Kraus, M.H., Bejar J. and Ron, D. (2007) Downregulation of Sef, an inhibitor of receptor tyrosine kinase signaling, is common to a vareity of human carcinomas. Oncogene 26, 6093–6098
6. Patel VN., Likar KM., Zisman-Rozen S., Cowherd SN., Lassiter KS., Turnbull JE., Ron D. and Hoffman MP (2008). Specific heparan sulfate structures modulate FGF10 biological activity during submandibular gland branching morphogenesis J. Biol. Chem. 283, 9308-17
7. Ron, D., Fuchs Y. and Chorev, D. (2008) Know thy Sef, a novel class of feedback antagonists of receptor tyrosine kinase signaling. International Journal of Biochemistry and Cell Biology, 40, 2040-52