Cbl Proteins as Regulators of Tyrosine Kinase Signaling

Division Of Basic Sciences - Nci

Investigators

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Abstract

RTKs, such as EGFR, HER2, MET and RET, are often inappropriately active (due to mutation or overexpression) in a wide array of epithelial malignancies. My laboratory cloned two of the three members of the mammalian Cbl protein family and demonstrated that they are negative regulators of the EGFR in mammalian cells. We have shown that Cbl proteins are RING finger E3s and that all mammalian Cbl proteins mediate ubiquitination of the activated EGFR, resulting in the degradation of the activated EGFR signaling complex. Work in my lab, in collaborations with other laboratories, and by other investigators has shown the Cbl proteins regulate many RTKs and signaling pathways. In addition, my lab has contributed to the structure function analysis of the Cbl proteins. More recently my laboratory has identified and characterized proteins which interact with and modify the function of Cblc, the least well characterized Cbl protein, identified and are characterizing E2 proteins that interact with the Cbl proteins, and identified mutant forms of Cbl proteins in human and mouse epithelial tumors. Ongoing work: 1) i investigates the proteins that collaborate with Cbl proteins to mediate RTK downregulation by identifying proteins in the active complex by mass spec analysis. 2) a screen to identify Cblb E3 inhibitors; 3) Investigations on the function of TROP2 in TNBC and the mechanisms of downregualtion of TROP2. In a translational project we have found that EGFR is amplified in 2% of breast cancer tumors and that this protends a poor outcome. Further, we have found that the EGFR amplified tumors frequently have activating mutations in the PI3K pathway (40-70%). Ongoing work is 1) characterizing the ability of EGFR inhibitors +/- PIK3CA inhibitors to kill cells with mutations in these pathways in vitro and in vivo; and 2) evaluating the effects of these inhibitors on tumor initiating cells.