During previous cycles of this competing renewal we established the importance of autocrine ErbB family kinase stimulation in colon cancer cell lines. We also developed a sophisticated model in which we have translated these results into xenograft and orthotopic implantation systems. Moreover, we have confirmed that colon cancer metastases from patients reflect the ErbB phenomena we have seen in models. ? A key observation has been that maintenance of the malignant phenotype of colon cancer cells is not dependent upon the amplitude of ErbB signaling. Instead it is the constitutive nature of ErbB family activation that persists in the absence of exogenous ligands that is linked to the malignant phenotype. Characterization of this endogenous activation has allowed us to identify ErbB receptor docking sites that are dependent upon autocrine mechanisms in growth arrest. The hypothesis that these constitutively activated sites are responsible for survival and malignant behavior of colon cancer cells will be tested in Specific Aim I. ? Other studies showed that ErbB2 cooperates with the EGFR in promoting malignancy of colon cancer cells. Specifically, the Y1248 docking site of ErbB2 was found to be autoactivated upon heterodimerization with EGFR. This site specifies signaling modules which are not reiterated by heterodimerized EGFR. The hypothesis that endogenous activation of ErbB2 Y1248 plays a key role in survival and malignant behavior of colon cancer cells will be tested in Specific Aim II. Activation of signal transduction pathways from ErbB family docking sites requires the binding of their specific adaptor molecules. The hypothesis that the specific subset of adaptors binding to endogenously activated docking sites is critical to the survival and malignant behavior of colon cancer cells will be tested in Specific Aim III.
The Specific Aims of this project are: I) Determine whether endogenously activated EGFR docking sites are critical for maintaining the malignant phenotype of colon cancer. II) Determine whether activation of ErbB2 Y1248 is critical to the maintenance of malignancy in colon carcinoma. Ill) Determine whether a specific subset of adaptor proteins linked to endogenously activated ErbB docking sites is critical to maintenance of malignancy in colon cancer. ? ?
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