Perelman School of Medicine Affiliations
Chair, Biochemistry & Molecular BiophysicsGraduate Group
B.A., University of Oxford, 1987
M.Phil, Yale University, 1992
Ph.D., Yale University, 1996
Burroughs Wellcome Fund Career Award in Biomedical Sciences, 2001
Howard Temin Award from National Cancer Institute, 2001
Dennis and Marsha
Dammerman Scholar of the Damon Runyon Cancer Research Foundation, 2006
Michael S. Brown New Investigator Research Award, 2008
We are interested in understanding molecular mechanisms that regulate receptor signaling at and across membranes. We continue our long-standing interest in the regulation of the Epidermal Growth Factor Receptor (EGFR) family of receptor tyrosine kinases (RTKs), and also expand our study to several other families of RTKs. Rekindling an early interest in pleckstrin homology domains, we are also investigating the role of lipid binding modules in several settings. To address these questions we use a combination of biophysical, structural, biochemical and cellular approaches.
1. Activation and inhibition of Epidermal Growth Factor Receptor (EGFR).
EGFR is an important and clinically validated cancer target. Despite many years of study, there remain significant questions about the mechanism of activation of EGFR, and its dysregulation in cancer. Using X-ray crystallography as a primary tool, we have elucidated the mechanisms of action of several clinically relevant EGFR antibodies, including cetuximab and necitumumab. We have also shown that nanobodies or VHH domains, the smallest natural antigen-binding modules (from heavy chain only camelid antibodies), can inhibit EGFR either by mimicking existing antibodies or through unique mechanisms - emphasizing the power of nanobodies as possible ‘designer inhibitors’ and as tools for asking mechanistic questions about their binding targets. Current efforts in this area focus on the use of antibodies and nanobodies to understand oncogenically activated EGFR.
A subset of the oncogenically activated EGFR mutations that have been identified from patient samples lie in the extracellular region of the receptor. We currently have no molecular understanding of how these mutations activate of the receptor. To address this we are investigating, in collaboration with Mark Lemmon, how the extracellular and intracellular regions of EGFR are coupled.
2. RTKs with membrane proximal FNIII domains.
Mounting data indicate far more mechanistic diversity across the RTK superfamily than previously thought, and we are also interested in several other families of RTKs. In one project, we are analyzing the roles of membrane-proximal fibronectin type III (FNIII) domains (found in 23/58 RTKs, including Tie2). In collaboration with Mark Lemmon, we are trying to understand the relationship between oligomerization of Tie receptors and receptor activation state.
3. Regulatory roles of lipid binding modules.
In collaboration with Christopher Burd, we are investigating the roles of Vps74 and its human homologue, GOLPH3 in phosphoinositide regulation of protein sorting in the Golgi. In particular we are interested in the relationships between phosphoinositide binding, induced membrane curvature and protein sorting. In a second direction we are evaluating the role of lipid modulated effector domains (e.g. KA1) in kinase regulation.
Atrish Bagch – Ph.D. Student, BMB
Ryan Emptage, Ph.D. – Postdoctoral Fellow
Yu-San Huoh, Ph.D. – Postdoctoral Fellow
Sravya Kotaru – M.S. Student, BE
Jason Moore, Ph.D – Postdoctoral Fellow (joint with Mark Lemmon)
Lemmon, M.A., Schlessinger, J., & Ferguson, K.M.: The EGFR Family: Not So Prototypical Receptor Tyrosine Kinases. Cold Spring Harb. Perspect. Biol. 6: a020768, 2014.
Schmitz, K.R., Bagchi, A., Roovers, R.C., van Bergen en Henegouwen, P.M.P., & Ferguson, K.M. Structural evaluation of EGFR inhibition mechanisms for nanobodies/VHH domains. Structure 21, 1214-1224, 2013.
Wood C.S., Schmitz K.R., Bessman N.J., Setty T.G., Ferguson K.M., & Burd C.G. PtdIns4P recognition by Vps74/GOLPH3 links PtdIns 4-kinase signaling to retrograde Golgi trafficking. J. Cell Biol. 187: 967-975, 2009.
Schmitz, K.R., Liu, J., Li, S., Setty, T.G., Wood, C S., Burd, C.G. & Ferguson, K.M. Golgi localization of glycosyltransferases requires a Vps74p oligomer. Dev. Cell 14: 523-534, 2008.
Li, S., Schmitz, K.R., Jeffrey, P.D., Wiltzius, J.J., Kussie, P. & Ferguson, K.M. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7: 301-311, 2005.
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