Yehenew M. Agazie

Biography

Works as Professor of Biochemistry.

Research Interest

More often than not, cell transformation, tumor initiation, and cancer development arises from deregulation of normal cellular signaling and homeostasis. Two of the signaling pathways commonly deregulated in cancer are the receptor tyrosine kinase (RTK) and the Wnt/β-catenin signaling pathways. My lab focuses on the role of the Src homology phosphotyrosyl phosphatase 2 (SHP2) in these two signaling pathways. The long-term objectives are a) to define the molecular mechanism of SHP2 in promoting mitogenic and cell survival signaling induced by the RTK and the Wnt/β-catenin signaling pathways, b) to genetically test the importance of SHP2 in breast tumor initiation and progression to malignancy, c) to investigate if SHP2 plays a critical role in breast cancer stem cell survival, self renewal and tumor initiation, and d) to study the role of SHP2 in triple/basal-type breast cancer. In addition, my lab is involved in characterizing SHP2 as a therapeutic target for the treatment of breast cancer, and in discovering and developing SHP2-specific inhibitors that will serve as leads for future development of anti-SHP2 drugs. Specific areas of focus are as outlined below. The Role of SHP2 in EGFR/HER2 Signaling and its Implication in Breast Cancer. The positive role of SHP2 in receptor tyrosine kinase signaling is well documented, but its molecular mechanism remains to be elucidated. The specific objectives are a) to investigate the molecular mechanism of SHP2 in promoting EGFR/HER2 signaling, b) to study how SHP2 promotes cell growth and transformation under cell culture conditions, and c) to analyze the importance of SHP2 in HER2-induced mammary tumorigenesis in breast cancer model mice. The role of SHP2 in promoting the Wnt/β-catenin signaling pathway: β-Catenin is the major transducer of the Wnt signaling pathway. The binding of the Wnt ligand to the FZ-LRP5/6 co-receptors induces the release of beta catenin from adherens junction, leading to an increase in its cytoplasmic pool and translocation to the nucleus. It then interacts with the TCF/LEF1 family of DNA binding proteins and induces the transcription of target genes. Our preliminary findings suggest that SHP2 is important for beta catenin activation. We are currently investigating the molecular mechanism for SHP2 in mediating this biochemical event. These findings will strengthen the notion that SHP2 plays pivotal roles in signaling pathways that are frequently implicated in cancer. The Role of SHP2 in Cell Adhesion and Motility and Actin Cytoskeletal Dynamics. SHP2 regulates cell adhesion and motility induced by the binding of integrins (cell-surface receptors) to the extracellular matrix (ECM). In addition, SHP2 regulates actin cytoskeletal reorganization by modulating the activity of the small GTP-binding protein Rho. Again, the molecular basis for the role of SHP2 in these pathways is poorly understood primarily because target substrates have not been identified. The third line of my research focuses on isolation, identification and characterization of SHP2 substrates involved these cellular processes. Currently, we are isolating and identifying these substrates by a combination of affinity precipitation, western blotting and mass spectroscopy. These results will provide a mechanistic explanation as to how SHP2 promotes cell migration, establishing the relevance of SHP2 in tumor malignancy. SHP2 Inhibitory Therapeutics: We are currently testing the importance of SHP2 in oncogene-induced mammary tumorigenesis by crossbreeding SHP2 conditional knockout mice with breast cancer models. In addition, we are investigating the significance of SHP2 inhibition in the treatment of breast cancer. We employ retrovirus mediated expression of anti-SHP2 shRNA, anti-SHP2 peptides and peptidomimetic anti-SHP2 molecules to prove the concept that inhibition of SHP2 might provide an alternative strategy for breast cancer chemotherapy. The long term goal is to come up with a lead compound for developing anti- SHP2 drugs.