Lewis T. Williams
Walking Fish Therapeutics, Inc.
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Primary Section: 41, Medical Genetics, Hematology, and Oncology Membership Type:
Member
(elected 1997)
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Research Interests
By purifying receptors for platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) and by cloning their cDNAs, my laboratory discovered two new classes of receptors. Also, we cloned the first cDNA for the vascular endothelial growth factor receptor family. These receptors are important in mediating the effects of growth factors in atherosclerosis, embryonic development, wound healing and angiogenesis. We pioneered the use of dominant negative receptors to block these responses in vivo. Mutations in receptors discovered by by my laboratory have recently been shown to cause three human genetic diseases. My laboratory was the first to discover the general principle that, upon binding ligand, growth factor receptors form a physical complex with cytoplasmic signaling molecules and showed that each signaling molecule binds to a highly specific "docking site" on the receptor that includes an autophosphorylated tyrosine and its flanking sequences. These findings provided a general paradigm for the early steps in signal transduction by tyrosine kinase family of receptors. During the course of this work we found that one intracellular signaling molecule, PI 3-kinase, is especially important in mediating signals from PDGF receptors. We showed that mutated receptors that were unable to bind and activate PI 3-kinase, could not trigger cell proliferation even though they could activate a number of other cellular responses. My group then cloned the first cDNA of a subunit of PI 3-kinase and demonstrated at a molecular level how the activity of PI 3-kinase is regulated through subunit interactions. Later we demonstrated a novel mechanism by which PI 3-kinase stimulates intracellular mitogenic pathways and found that a specific phospholipid product of PI 3-kinase binds directly to a domain of a key enzyme that regulates proliferation and causes a conformational chance in the enzyme. Once again this appears to be a paradigm for how members of this growing family of PI 3-kinase can regulate cellular processes. This family has recently been found by others to regulate translation, call cycle progression, cell responses to DNA damage and senescence (in simple organisms). It is likely that mechanisms similar to those discovered in my laboratory are involved in the regulation of these processes by PI 3-kinase family members.
