Semester

Fall

Date of Graduation

2013

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Yehenew M. Agazie

Committee Co-Chair

Peter M. Gannett

Committee Member

John M. Ruppert

Committee Member

Michael D. Schaller

Committee Member

Xiaodong Shi

Abstract

The Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) has been established as a critical mediator of cancer-related cell signaling downstream of receptor tyrosine kinases like EGFR and HER2. As such, targeting of SHP2 is being recognized as a potentially viable therapeutic option in HER2-positive and triple-negative breast cancers. In this report, I employed molecular and cellular biology techniques to further elucidate the role of SHP2 downstream of receptor tyrosine kinases in breast cancer cell lines. In this way, I was able to contribute knowledge to how SHP2 controls triple-negative cell motility. In addition, the mechanism of SHP2 control of HER2 signaling was investigated in order to better understand how SHP2 positively mediates signaling. The EGFR/HER2 heterodimerization axis was also explored, uncovering a mechanism by which HER2 is able to protect EGFR from degradation through suppression of phosphorylation at specific sites. Finally, molecular modeling was used to determine how SHP2 is able to selectively interact with endogenous substrates. These studies contribute both to the rationale for targeting SHP2 and the mechanism by which SHP2 promotes breast cancer signaling in cooperation with EGFR and HER2. The knowledge added by these studies will hopefully contribute in the future toward the development of selective small molecule inhibitors of SHP2.

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