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. Ongoing work: 1) we investigate the proteins that collaborate with Cbl proteins to mediate RTK downregulation by identifying proteins in the active complex by mass spec analysis. We have identified that the scaffold protein flotillin 2 (flot2) associates with the EGFR and it prevents activation and down regulation of the EGFR Loss of flot2 results in increased EGFR activation, increased Cbl protein mediated down regulation, and increased growth of tumors driven by EGFR (Wisneiwski et al., J Biol Chem 299(1) 102766, 2023). In ongoing work we are investigating the effects of flot2 on HER2, a member of the EGFR family that is frequently amplified in breast cancer. Preliminary data indicate that flot2 inhibits HER2 internalization and downregulation, thus prolonging the signaling from amplified HER2. Mechanistic studies and the clinical implications of this interaction are being evaluated. 2) we had conducted a screen to identify Cblb E3 inhibitors and while we had found compounds that inhibited Cblb E3 activity, none were sufficiently potent enough or selective enough for further investigation. There are several companies now developing Cblb inhibitors for clinical use. We have established a CRADA with Glenmark Pharmaceuticals Limited to test their Cblb inhibitor in breast cancer models as a single agent and in combination with other therapies. This work is ongoing.