We are investigating the function of Cbl proteins, a family of proteins that regulate tyrosine kinase activity. Cbl proteins belong to the RING finger class of ubiquitin protein ligases (E3s) and function as E3s for activated tyrosine kinases. My group cloned two of the three mammalian Cbl genes (Cblb and Cblc) and demonstrated that all mammalian Cbl proteins mediate ubiquitination and degradation of the activated epidermal growth factor receptor (EGFR) as well as other components of the signaling complex. Ongoing work is focused on understanding the biochemical and physiologic functions of the three mammalian Cbl proteins in epithelial cells and elucidating the differences in their specificity and/or function. We have been focused on the function of Cblc, the most recently identified family member about which the least is known. This protein is expressed only in epithelial cells and my group is particularly interested in epithelial malignancies such as breast cancer. Previously, to understand the function of the Cblc protein, we collaborated with Josef Penninger (IMBA, Vienna, Austria) to knock out Cblc. Unfortunately, the Cblc null mice have no detectable abnormalities. To gain insight into the function of Cblc, we have used yeast two-hybrid screens to detect novel proteins that interact with Cblc. Currently, we are characterizing the function of these proteins and the consequences of their interactions with Cblc. In addition, we have identified mutations in Cblc that is predicted to create a transforming version of Cblc from a murine breast cancer. We are investigating this mutant in more detail to see if it is transforming and searching for evidence of other mutants in murine and human tumors. More generally, ongoing work is characterizing the molecular mechanism by which the Cbl proteins mediate ubiquitination. This includes investigating the structure-function relationship of the Cbl proteins, and their interactions with the ubiquitin conjugating (E2) proteins. We have collaborated with the Randazzo group (CCR)to investigate the interaction between ARAP1, Cbl protiens, and EGFR trafficking. In addition we are collaborating with Marcus Clark (University of Chicago) to study the role of Cbl-b on B-Cell antigen receptor trafficking and with Jian Zhang to understand the function of Cbl-b in T-cell receptor signaling. Finally, we have an ongoing collaboration with Allan Weissman (CCR) on the general investigation of mechanisms by which the Cbl proteins function as E3s. Overall, these studies should provide insight into the biochemical, biological, and pathophysiological functions of the Cbl proteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010977-05
Application #
8552911
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$955,212
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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