Joint Fellowship Training Program
Mentor:
Gibbes Johnson, Ph.D. and Ying-Xin Fan, Ph.D.
Organizational Affiliation and Position:
Gibbes Johnson, Ph.D., Chief, and Ying-Xin Fan, Ph.D., Staff Fellow, Laboratory of Chemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research (CDER), FDA
Email:
gibbes.johnson@fda.hhs.gov
ying-xin.fan@fda.hhs.gov
Telephone:
(301) 827-1770
(301) 827-1763
Running Title of Program:
Molecular mechanisms of EGFR and ErbB2 kinase mutants in human cancers
Project Summary:
The ErbB family of receptors, including the epidermal growth factor receptor (EGFR; ErbB1), ErbB2, ErbB3 and ErbB4, play important roles in control of cell proliferation, migration, survival and differentiation. Dysregulation of ErbB receptor activity, especially EGFR and ErbB2, has been implicated in various human cancers. Accordingly, these receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets. However, relatively little is known regarding the molecular mechanisms by which the activity and specificity of the receptor kinases are regulated. Our lab current research interest is focused on the investigation of the activation mechanism of ligand- or mutation-induced activation of EGFR and ErbB2 kinases. Our research bridges enzymatic studies using physiological substrates, cellular signaling and structural biology. Our recent results have demonstrated that activation of EGFR or ErbB2 is accompanied by the change of the kinase specificity towards select downstream signaling proteins. We propose that the kinase activation results in an alteration of the kinase specificity, which in turn results in the pathway-selective stimulation of cell signaling.
Proposed Project for IOTF Fellow:
Recently, activating kinase domain mutations of EGFR and ErbB2 have been reported in many human carcinomas that are exquisitely responsive to ErbB-targeted drugs. The Fellow’s primary research will be focused on elucidation of the molecular mechanisms by which the oncogenic EGFR and ErbB2 mutants are activated. The Fellow will investigate the enzymology and cell signaling of the activating EGFR and ErbB2 mutations in cancer. Along with the pathway-selective activation, the down-regulation of EGFR and ErbB2 cancer mutants appears to be impaired. The Fellow will also have the opportunity to investigate the down-regluation mechanism of these EGFR and ErbB2 mutants. The laboratory is located on the NIH main campus in Bethesda, MD and provides access to excellent research resources, such as core facilities, library and seminars.
Regulatory Activity:
The Division of Therapeutic Proteins regulates a wide range of therapeutic proteins for the treatment of cancer. Drs. Johnson and Fan have extensive regulatory experience and the Lab of Chemistry has primary chemistry, manufacturing and controls review responsibilities for therapeutic enzymes used for oncology indications. Under the mentorship of Drs. Johnson and Fan, the Fellow will gain experience by participating in the quality review of drug applications as part of an interdisciplinary team to evaluate potential protein drugs for cancer.
Reference(s):
Fan, Y.X., Wong, L., Ding, J., Spiridonov, N.A., Johnson R.C. and Johnson, G.R. (2008) Mutational activation of Erbb2 reveals a new protein kinase autoinhibition mechanism. J. Biol. Chem. 283, 1588-1597.
Fan, Y.X., Wong, L. and Johnson, G.R. (2005) EGFR kinase possesses a broad specificity for ErbB phosphorylation sites and ligand increases turnover number without affecting substrate binding affinity. Biochem. J. 392, 417-423.
Fan, Y.X., Wong, L., Deb, T.B. and Johnson G.R. (2004) Ligand regulates epidermal growth factor kinase specificity: Activation increases preference for GAB1 and SHC versus autophosphorylation sites. J. Biol. Chem. 279, 38143–38150.
Wang, L.H., Yang, X.Y., Zhang X., Mihalic K., Fan Y.X., Xiao W., Howard, O.M., Appella, E., Maynard, A.T. and Farrar, W.L. (2004) Suppression of breast carcinoma by chemical modulation of the vulnerable zinc finger within estrogen receptor DNA binding domain. Nat. Med. 10, 40-47.
