Research Interests
Signaling by growth factor receptor tyrosine kinases, and inositol phospholipid signaling - biochemical, cellular, and structural biological studies.
Key words: growth factor receptor, phosphoinositide, signaling, cancer, structure, membrane recruitment.
Description of Research
Signaling by Growth Factor Receptor Tyrosine Kinases
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 and elsewhere have shown that EGF binding promotes conformational changes that induce 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 this hetero-oligomerization process using cellular, biochemical, and biophysical approaches. We are now especially interested in understanding how ErbB2/HER2/Neu is activated. This member of the family has no known ligand, yet is activated in trans by ligands for other family members – through receptor heteromerization. ErbB2 is overexpressed in some 30% of human breast cancer cases, and the value of Herceptin( TM) as a breast cancer drug has shown it to be an important therapeutic target. If we are able to understand the normal mechanism of ErbB2 regulation, we hope that this will suggest new pharmacological approaches for targeting this process that will not bring with them the disadvantages of HerceptinTM. Our approach to this is multidisciplinary, and currently draws substantially from insights gained from our recent structural studies.
Signal-Dependent Membrane Recruitment by Small Domains
The second main focus of the laboratory is on small (100 aa or so) 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, and have shown structurally how a subset of PH domains recognize the 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 in the human proteome. We have completed a genome-wide analysis of PH domains in S. cerevisiae in order to ascertain what other roles PH domains play. We are also studying lipid binding by some novel phosphoinositide-targeting domains. Our approaches again draw from biochemical, biophysical, and cell biological studies.
Lab personnel:
Steve Artim - V.M.D./Ph.D. Student, BMB
Nicholas Bessman - Ph.D. Student, BMB
Scott Bresler - M.D./Ph.D. Student, BMB
Pamela Burgess-Jones - Research Specialist
Jon Kenniston, Ph.D. - Jane Coffin Childs Postdoctoral Fellow
Jeannine Mendrola, Ph.D. - Research Associate
Jason Moore, Ph.D. - Postdoctoral Researcher
Alfonso Morales - Undergraduate Researcher
Katarina Moravcevic - Ph.D. Student, BMB
Camilla Oxley, D. Phil. - Postdoctoral Researcher
Jin Park - Ph.D. Student, BMB
Fumin Shi - Ph.D. Student, BMB
Neo Wu - Ph.D. Student, BMB
Selected Publications
Moravcevic, K., Mendrola, J.M., Schmitz, K.R., Wang, Y.-H., Slochower, D., Janmey, P.A. and Lemmon, M.A.: Kinase Associated-1 (KA1) Domains Drive MARK/PAR1 Kinases to Membrane Targets by Binding Acidic Phospholipids. Cell 143: 966-977, 2010.
Alvarado, D., Klein, D.E., and Lemmon, M.A.: Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor. Cell 142: 568-579, 2010.
Lemmon, M.A. & Schlessinger, J.: Cell signaling by receptor-tyrosine kinases. Cell 141: 1117-1134, 2010.
Kenniston, J.A. and Lemmon, M.A.: Dynamin GTPase regulation is altered by PH domain mutations found in centronuclear myopathy patients. EMBO Journal 29: 3054-3067, 2010.
Shi, F., Telesco, S.E., Liu, Y., Radhakrishnan, R., and Lemmon, M.A.: ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc. Natl. Acad. Sci. U. S. A. 107: 7692-7697, 2010.
Alvarado, D., Klein, D.E., and Lemmon, M.A.: ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Nature 461: 287-291, 2009.
Red Brewer, M., Choi, S.H., Alvarado, D., Moravcevic, K., Pozzi, A., Lemmon, M.A., and Carpenter, G.: The juxtamembrane region of the EGF receptor functions as an activation domain. Molecular Cell 34: 641-651, 2009.
Bethoney, K.A., King, M.C., Hinshaw, J.E., Ostap, E.M., & Lemmon, M.A.: A possible effector role for the pleckstrin homology (PH) domain of dynamin. Proc. Natl. Acad. Sci. U. S. A. 106: 13359-13364, 2009.
Klein, D.E., Stayrook, S.E., Shi, F., Narayan, K., & Lemmon, M.A.: Structural basis for EGFR ligand sequestration by Argos. Nature 453: 1271-1275, 2008.
Yu, J.W., Mendrola, J.M., Audhya, A., Singh, S., Keleti, D., DeWald, D.B., Murray, D., Emr, S.D., & Lemmon, M.A.: Genome-wide analysis of membrane targeting by S. cerevisiae pleckstrin homology domains. Molecular Cell 13: 677-688, 2004.
Klein, D.E., Nappi, V.M., Reeves, G.T., Shvartsman, S.Y., & Lemmon, M.A.: Argos inhibits EGF receptor signaling by ligand sequestration. Nature 430: 1040-1044, 2004.
Lemmon, M.A.: Membrane recognition by phospholipid-binding domains. Nature Reviews Molecular and Cellular Biology 9(2): 99-111, 2008.
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Last updated: 05/23/2013
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