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2005 Dean's Award for Excellence in Graduate Student Training 809C Stellar-Chance
Laboratories |
Research Interests of the Lemmon Lab: Signaling by Receptor Tyrosine Kinases from the ErbB/HER family: We are interested in understanding how growth factor receptors from the epidermal growth factor (EGF) receptor family signal across the membrane. For the EGF receptor itself, X-ray crystal structures recently determined in our lab (Ref 6) and elsewhere (Ref 5) have shown that EGF binding induces conformational changes that promote receptor dimerization (which is responsible for receptor activation). It is also known that the four members of the EGF receptor family, which includes EGF receptor, ErbB2 (also known as HER2/Neu), ErbB3, and ErbB4 from hetero-oligomers. We are now trying to understand ErbB receptor hetero-oligomerization using cellular, biochemical, and biophysical approaches, with a view to devising new approaches to inhibit these receptors when they are activated in cancer. EGF Receptor Signaling in Drosophila: We are collaborating with Stas Shvartsman (Princeton) and Joseph Duffy (Indiana U.) in efforts to construct quantitative models of how EGF receptor signaling controls patterning in Drosophila development. This entails a multidisciplinary approach ranging from biochemistry/biophysics/structural biology (in our lab), computational modeling (Shvartsman lab), and Drosophila genetics (Duffy and Shvartsman labs). In our studies so far we have established that Argos, a natural inhibitor of EGFR signaling in Drosophila, acts by sequestering growth factor ligands (Ref 1). The implications of this for precise control of EGFR signaling at different developmental stages are now being studied by the 3 laboratories. We are also trying to determine whether “anti-EGF” molecules like Argos exist in humans, or whether functional equivalents can be developed for use in treating EGFR-dependent cancers. Membrane Recruitment by Phosphoinositide-Binding Domains: Another main focus of the laboratory is on small protein domains in signaling, cytoskeletal, and other proteins that recognize membrane components and target their host proteins to cellular membranes. To date we have worked primarily with pleckstrin homology (PH) domains (eg Refs 4 & 7), and have shown structurally how a subset of PH domains recognize lipid products of agonist-dependent phosphoinositide 3-kinases, and so can drive acute recruitment of their host proteins to the plasma membrane. The PH domain is the 11th most common domain the human proteome. We now know that, while several bind to specific phosphoinositides, many (most) PH domains do not. In fact, our recent genome-wide analysis of PH domains in S. cerevisiae (Ref 4) showed that only a fraction of PH domains bind phosphoinositides. We are currently combining biochemical and yeast genetics approaches to identify what other roles PH domains play. In addition to PH domains, we are also interested in the roles of FYVE domains, phox homology (PX) domains, and other modules and proteins that bind specifically to phosphoinositides. In a genome-wide study, we showed that all yeast PX domains bind phosphatidylinositol-3-phosphate, a lipid found in endosomal compartments (Ref 8) - although with widely differing affinities. In collaboration with Stephen Dove and colleagues at the University of Birmingham, UK, we are also studying the recognition of phosphatidylinositol-3,5-bisphosphate by a novel family of β-propeller proteins involved in autophagy and other trafficking processes (Ref 3). In each of these cases, our approaches draw from biochemical, biophysical, and cell biological studies. Dynamin-Family Large GTPases in Intracellular Trafficking: A developing area in the laboratory is an effort to understand how GTP-regulated assembly and disassembly of large GTPases such as dynamin is linked to their roles in endocytosis (dynamin), mitochondrial fission (Dnm1p/DRP1), and possible control of nucleocytoplasmic trafficking (MxB; Ref 2). In each case we are combining biochemical/biophysical approaches with cellular and yeast genetic studies. Our focus is on putative effector domains within the large GTPase molecule, and how these are linked to other cellular components, such as phosphoinositides in the case of dynamin. RECENT REPRESENTATIVE PUBLICATIONS
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