Center for Bioinformatics at KU

As part of our public Seminar Series
http://bioinformatics.ku.edu/seminars

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

Dr. Moosa Mohammadi

Department of Pharmacology, New York University Langone Medical Center

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

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.