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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 and elsewhere 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 this hetero-oligomerization process using cellular, biochemical, and biophysical approaches. Above all, we are 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 Herceptin^TM. 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 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. We have recently embarked on a genome-wide analysis of PH domains in S. cerevisiae in order to ascertain what other roles PH domains play.

In addition to PH domains, we are also interested in the roles of FYVE domains and phox homology (PX) domains, which bind to phosphatidylinositol-3-phosphate, a lipid found in endosomal compartments. We have analyzed all S. cerevisiae PX domains, and are currently assessing their physiological roles.

A current focus in work on these domains is to test the hypothesis, suggested by several observations, that PH and PX domains may act as ‘coincidence’ detectors, effectively checking for the coincidence of a particular protein target and lipid target in the same cellular compartment. Our approaches again draw from biochemical, biophysical, and cell biological studies.

Selected Publications:

Klein DE, Nappi VM, Reeves GT, Shvartsman SY, and Lemmon MA. (2004) "Argos inhibits epidermal growth factor receptor signalling by ligand sequestration." Nature 430:1040-1044

Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, Yokoyama S. (2003) "An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors." Molecular Cell 12:541-52.

Ferguson, K.M., Berger, M.B., Mendrola, J.M., Cho, H.-S., Leahy, D.J., and Lemmon, M.A. (2003) "EGF activates its receptor by breaking interactions that auto-inhibit ectodomain dimerization." Molecular Cell 11:507-517.

Lemmon, M.A. (2003) "Phosphoinositide recognition domains" Traffic 4:1-13.

Baumeister, M.A., Martinu, L., Rossman, K.L., Sondek, J., Lemmon, M.A., and Chou, M.M. (2003) "Loss of PtdIns-3-P binding by the C-terminal Tiam-1 pleckstrin homology (PH) domain prevents in vivo Rac1 activation without affecting membrane targeting." J. Biol. Chem 278:11457-64 .

Yu, J.W., and Lemmon, M.A. (2003) "Genome-wide analysis of signaling domain function." Curr. Opin. Chem. Biol. 7:103-109.

Mendrola, J.M., Berger, M.B., King, M.C., and Lemmon, M.A. (2002) "The single transmembrane domains of erbB receptors self-associate in cell membranes." J. Biol. Chem. 277:4704-4712.

Yu, J.W., and Lemmon, M.A. (2001) "All phox homology (PX) domains from Saccharomyces cerevisiae specifically recognize phosphatidylinositol-3-phosphate." J. Biol. Chem. 276:44179-44184.

Sankaran, V.G., Klein, D.E., Sachdeva, M.M., and Lemmon, M.A. (2001) "High-affinity binding of a FYVE domain to phosphatidylinositol 3-phosphate requires intact phospholipid but not FYVE domain oligomerization." Biochemistry 40:8581-8587.

Ferguson, K.M., Darling, P.J., Macatee, T.L., Mohan, M., and Lemmon, M.A. (2000) "Extracellular domains drive homo- but not hetero-dimerization of erbB receptors." EMBO J. 19:4632-4643.

Lemmon, M.A. and Ferguson K.M. (2000) "Signal-dependent membrane-targeting by pleckstrin homology (PH) domains." Biochem. J. 350:1-18.

Ferguson, K.M., Kavran, J.M., Sankaran, V., Fournier, E., Isakoff, S.J., Skolnik, E.Y., and Lemmon, M.A. (2000) "Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology (PH) domains." Molecular Cell 6:373-384.

Lee, A., Frank, D.W., Marks, M.S., and Lemmon, M.A. (1999) "Dominant-negative inhibition of receptor-mediated endocytosis by dynamin-1 with a defective PH domain." Curr. Biol. 9:261-264.