Mark A. Lemmon, Ph.D
Professor of Biochemistry and Biophysics
Department: Biochemistry and Biophysics
Graduate Group Affiliations
Contact information
809C Stellar-Chance Labs
422 Curie Blvd.
Philadelphia, PA 19104-6059
422 Curie Blvd.
Philadelphia, PA 19104-6059
Office: (215) 898-3072
Fax: (215) 573-4764
Fax: (215) 573-4764
Email:
MLEMMON@MAIL.MED.UPENN.EDU
MLEMMON@MAIL.MED.UPENN.EDU
Publications
Links
Search PubMed for articles
Cell and Molecular Biology graduate group faculty webpage.
Biochemistry and Molecular Biophysics graduate group faculty webpage.
Search PubMed for articles
Cell and Molecular Biology graduate group faculty webpage.
Biochemistry and Molecular Biophysics graduate group faculty webpage.
Education:
B.A. (Biochemistry)
Hertford College, University of Oxford, UK (Hons), 1988.
M.Phil. (Biophysics/Biochemistry)
Yale University, New Haven, CT, 1990.
Ph.D. (Biophysics/Biochemistry)
Yale University, New Haven, CT, 1993.
(Pharmacology)
New York University Medical Center, New York, NY, 1996.
Permanent linkB.A. (Biochemistry)
Hertford College, University of Oxford, UK (Hons), 1988.
M.Phil. (Biophysics/Biochemistry)
Yale University, New Haven, CT, 1990.
Ph.D. (Biophysics/Biochemistry)
Yale University, New Haven, CT, 1993.
(Pharmacology)
New York University Medical Center, New York, NY, 1996.
Description of Research Expertise
Research InterestsSignaling 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:
Diego Alvarado, Ph.D. - Damon Runyon Postdoctoral Fellow
Katarina Moravcevic - Ph.D. Student, BMB
Sung Hee Choi - Ph.D. Student, BMB
Fumin Shi - Ph.D. Student, BMB
Nicholas Bessman - Ph.D. Student, BMB
Jon Kenniston, Ph.D. - Jane Coffin Childs Postdoc Fellow
Jeannine Mendrola, Ph.D. - Research Associate
Daryl E. Klein - M.D./Ph.D. Student, BMB
Pamela Burgess-Jones - Research Specialist
Selected Publications
Lemmon, M.A. & Schlessinger, J.: Mechanisms of activation and cell signaling by receptor-tyrosine kinases. Cell Page: in press, 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.
Lemmon, M.A.: Membrane recognition by phospholipid-binding domains. Nature Reviews Molecular and Cellular Biology 9(2): 99-111, 2008.
Dawson, J.P., Bu, Z., Lemmon, M.A.: Ligand-induced structural transitions in ErbB receptor extracellular domains. Structure 15: 942-954, 2007.
Choi, S.H., Mendrola, J.M., Lemmon, M.A.: EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer. Oncogene 26(11): 1567-1576, 2007.
Dawson, J.P., Berger, M.B., Lin, C.C., Schlessinger, J., Lemmon, M.A., Ferguson, K.M.: Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Molecular and Cellular Biology 25: 7734-7742, 2005.
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.
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.
Dove, S.K., Piper, R.C., McEwen, R.K., Yu, J.W., King, M.C., Hughes, D.C., Thuring, J., Holmes, A.B., Cooke, F.T., Michell, R.H., Parker, P.J., & Lemmon, M.A.: Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J 23: 1922-1933, 2004.
Ferguson, K.M., Berger, M.B., Mendrola, J.M., Cho, H.-S., Leahy, D.J., & Lemmon, M.A.: EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Molecular Cell 11: 507-17, 2003.