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Mammalian cell biology: signaling regulation of protein ectodomain shedding. sexually transmitted infection: molecular biology and inhibition of ChlamydiaeResearch Interests: 1. Mammalian Cell Biology: Signaling Regulation of Protein Ectodomain Shedding Numerous transmembrane proteins undergo regulated proteolytic cleavage at the cell surface to release their extracellular domains. Ectodomain "shedding" of cell surface molecules generates soluble growth factors. cytokines. proteases. receptors and adhesins. and consequently regulates cell proliferation. differentiation. migration. and apoptosis. While normal physiological processes including development. immunity and wound healing requires ectodomain shedding. its disregulation contributes to the development of cancer. inflammatory and autoimmune reactions. cardiovascular disease and neurodegeneration. Aiming at the intervention of the development of these diseases. we study the signaling mechanisms that underlie the regulation of ectodomain shedding under a variety of physiological and pathological conditions. 2. Sexually Transmitted Infection: Chlamydial Cellular and Molecular Parasitology Chlamydiae are Gram-negative eubacteria that replicate strictly inside eukaryotic cells. They are the most prevalent cause of sexually transmitted infections and preventable blindness. Even though most chlamydial STIs are asymptomatic or manifest only mild urogenital inflammation. they often results in devastating complications including infertility. chronic pelvic pain. ectopic pregnancy. premature birth and arthritis. Chlamydial STIs also predispose individuals to HIV infection. We have recently identified peptide deformylase as an essential enzyme for chlamydial growth. We are characterizing this enzyme and exploring its inhibition for prevention and treatment of chlamydial diseases. We are also interested in identifying novel host factors that support chlamydial infection. Selected PublicationsLi X, Pérez L, Pan Z, Fan H. (2007) The transmembrane domain of TACE regulates protein ectodomain shedding. Cell Res. 17(12):985-98. Balakrishnan A, Wang L, Li X, Ohman-Strickland P, Malatesta P, Fan H. (2007) Inhibition of chlamydial infection in the genital tract of female mice by topical application of a peptide deformylase inhibitor. Microbiol Res. Oct 23. [Epub ahead of print] Perez L, Kerrigan JE, Li X, Fan H. (2007) Substitution of methionine 435 with leucine, isoleucine, and serine in tumor necrosis factor alpha converting enzyme inactivates ectodomain shedding activity. Biochem Cell Biol. 85(1):141-149. Zhang Q. Thomas SM. Lui VW. Xi S. Siegfried JM. Fan H. Smithgall TE. Mills GB. Grandis JR. (2006)Phosphorylation of TNF-alpha converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation. Proc Natl Acad Sci U S A. 103(18):6901-6. http://www.pnas.org/cgi/content/full/103/18/6901 Balakrishnan. A.. Patel. B. Sieber. SA. Chen. D. Pachikara. N. Zhong. G. Cravatt. BF and Fan. H. (2006). Metalloprotease inhibitors
GM6001 and TAPI-0 inhibit the obligate intracellular human pathogen Chlamydia trachomatis by targeting peptide deformylase of the
bacterium. J. Biol. Chem.
J. Biol. Chem. 281:16691-16699. Li. X.. Fan. H. (2004). Loss of ectodomain shedding due to mutations in
the metalloprotease and cysteine-rich/disintegrin domains of the tumor
necrosis factor-{alpha} converting enzyme (TACE). J. Biol. Chem.
279:27365-75. Fan. H.. Turck. C.W.. Derynck. R. (2003). Characterization of growth
factor-induced serine phosphorylation of tumor necrosis factor-{alpha}
converting enzyme (TACE) and of an alternatively translated polypeptide.
J. Biol. Chem. 278:18017-18027. Shi. W.. Fan. H.. Shum. L.. Derynck. R. (2000). The tetraspanin CD9
associates with transmembrane TGF-{alpha} and regulates TGF-{alpha}
-induced EGFR activation and cell proliferation. J. Cell Biol.
148:591-602. Fan. H.. Derynck. R. (1999). Ectodomain shedding of TGF-{alpha} and
other transmembrane proteins is induced by receptor tyrosine kinase
activation and MAP kinase signaling cascades. EMBO J. 18. 6962-6972. |
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