Department of Biochemistry



Yehenew M. Agazie DVM, PhD

D. V. M , Addis Ababa University, Ethiopia
Ph. D., University of Saskatchewan, CANADA
Postdoctoral Training:
University of Missouri, MO,
and Stony Brook University, NY

Assistant Professor of Biochemistry and Cancer Cell Biology
Department of Biochemistry
West Virginia University
Robert C. Byrd Health Sciences Center
Morgantown, WV 26506-9142
Phone; (304) 293-7756
Fax: (304) 293-6846
E-mail: yagazie@hsc.wvu.edu

Research:

Research in Agazie lab is supported by NIH/NCI.

Areas of Focus

More often than not, cell transformation, tumor formation and cancer development arises from disregulation of normal cellular signaling and homeostasis. Two of the signaling pathways commonly disregulated in cancer are the receptor tyrosine kinase 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 goals are to define the molecular mechanism and to develop anti-SHP2 therapeutics. Specific areas of focus are as outlined below.

1. 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.
    
2. The role of SHP2 in promoting the Wnt/β-catenin signaling pathway. Beta 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.
    
3. 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.
    
4. SHP2 Inhibitory Therapeutics: We are currently testing 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.

Selected Publications:

• Zhou, X., Zhang, M. and Agazie, YM (2008), Molecular Mechanism for SHP2 in
  Mediating HER2-Induced Signaling and Cell Transformation, Submitted.
   

• Zhou, X. and Agazie, Y. M. (2008), Inhibition of SHP2 in Breast Cancer Cells Leads
  to Mesenchymal to Epithelial Transition and Induces Reversion to a Normal
  Mammary Epithelial Phenotype, Cell Death Differ 15:988-96.
   

• Zhou, X., Coad, J., Ducatman, B. and Agazie, Y. M. (2008), The SHP2 Protein is
  Overexpressed in Breast Cancer Cell Lines and Infiltrating Ductal Carcinoma of the
  Breast, Implying its Involvement in Breast Cancer Development, Histopathology, In
  Press.
   

• Burks J. and Agazie YM (2006) Modulation of alpha-catenin Tyr phosphorylation by
  SHP2 positively effects cell transformation induced by the constitutively active
  FGFR3. Oncogene, 25:7166-7179
   

• Merritt, R., Hayman, M. J. and Agazie, Y. M. (2006), Mutation of Thr466 in SHP2
  Abolishes its phosphatases Activity, but Provides a New Substrate-Trapping, BBAMol. Cell Res. 1763: 45-56.
   

• Agazie, Y. M. and Hayman, M. J. (2003), Development of a New Trapping Mutant of SHP2 that Identifies EGFR, Gab1 and Three Other phosphotyrosyl Proteins as Target Substrates, J. Biol. Chem. 278: 13952-13958.
   

• Agazie, Y. M., and Hayman, M. J., (2003) Role of SHP2 in Transformation Induced
  by the Oncogenic Fibrobast Growth Factor Receptor 3, Oncogene, 22: 6909-6918.
   

• Agazie, Y. M. and Hayman, M. J. (2003), Molecular Mechanism for the Role of the
  Phosphotyrosyl Phosphatase SHP2 in the Epidermal Growth Factor Receptor
  Signaling, Mol. Cell. Biol., 23: 7875-7886.
   

• Agazie, Y. M., Ischenko, I., and Hayman, J. M., (2002), Concomitant Activation of
  the PI3K-Akt and Ras-ERK Signaling Pathways is Essential for Transformation by
  the V-SEA Tyrosine Kinase Oncogene, Oncogene 21:697-707.
   

• Agazie, Y. M., Bagot, J. C., Trickey, E. and Wilden, P. (2001), Molecular
  Mechanisms of ATP and Insulin Synergistic Stimulation of Coronary Artery Smooth
  Muscle Growth, Am. J. Physiol., Heart Circ. Physiol. 280: H795-H801.