College of Liberal Arts & Sciences

Molecular Mechanisms of FGF Receptor Regulation in Development and its Corruption in Disease

February 24, Tue 2009
1:00 pm, MRB 100 Conference Room

Dr. Moosa Mohammadi

Department of Pharmacology, New York University Langone Medical Center

Cellular signaling by the fibroblast growth factor (FGF) family of ligands (FGF1-10, and FGF16-23) plays ubiquitous roles in mammalian development and metabolism. FGFs execute their diverse activities by binding, dimerizing and activating FGF receptor tyrosine kinases (FGFRs) in a heparan sulfate (HS)-dependent fashion. Reflective of the pleiotropic roles of FGF signaling in human biology, deregulated FGF signaling leads to a wide array of human diseases, including skeletal, olfactory/reproductive syndromes, hearing loss, phosphate wasting disorders, and cancer. Consequently, there is a major impetus to comprehend the mechanisms of FGF signaling at the structural level as the results of such studies should facilitate the development of novel therapeutics for the treatment of a variety of human diseases. Crystallographic data from our laboratory have provided key static views of the molecular mechanisms of FGFR regulation, including the mechanism of HS-assisted FGF-FGFR dimerization, molecular determinants of FGF-FGFR binding specificity and promiscuity, novel auto-regulatory mechanisms in both the ectodomain and intracellular tyrosine kinase domain, and a crystallographic snapshot of the universal process of tyrosine trans-phosphorylation. Importantly, these studies have also unveiled the mechanisms by which naturally occurring mutations corrupt receptor function to give rise to various human pathologies.

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