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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010977-06
Application #
8763291
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$981,727
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Li, Minghui; Kales, Stephen C; Ma, Ke et al. (2016) Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation. Cancer Res 76:561-71
Liyasova, Mariya S; Ma, Ke; Lipkowitz, Stanley (2015) Molecular pathways: cbl proteins in tumorigenesis and antitumor immunity-opportunities for cancer treatment. Clin Cancer Res 21:1789-94
Veselits, Margaret; Tanaka, Azusa; Lipkowitz, Stanley et al. (2014) Recruitment of Cbl-b to B cell antigen receptor couples antigen recognition to Toll-like receptor 9 activation in late endosomes. PLoS One 9:e89792
Qiao, Guilin; Ying, Haiyan; Zhao, Yixia et al. (2014) E3 ubiquitin ligase Cbl-b suppresses proallergic T cell development and allergic airway inflammation. Cell Rep 6:709-23
Ryan, Philip E; Kales, Stephen C; Yadavalli, Rajgopal et al. (2012) Cbl-c ubiquitin ligase activity is increased via the interaction of its RING finger domain with a LIM domain of the paxillin homolog, Hic 5. PLoS One 7:e49428
Guo, Hui; Qiao, Guilin; Ying, Haiyan et al. (2012) E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity. Cell Rep 1:472-82
Kales, Stephen C; Ryan, Philip E; Lipkowitz, Stanley (2012) Cbl exposes its RING finger. Nat Struct Mol Biol 19:131-3
Yoon, Hye-Young; Kales, Stephen C; Luo, Ruibai et al. (2011) ARAP1 association with CIN85 affects epidermal growth factor receptor endocytic trafficking. Biol Cell 103:171-84
Lipkowitz, Stanley; Weissman, Allan M (2011) RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat Rev Cancer 11:629-43
Ryan, Philip E; Sivadasan-Nair, Nina; Nau, Marion M et al. (2010) The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating affinity for the ubiquitin-conjugating enzyme. J Biol Chem 285:23687-98

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