My laboratory studies signal transduction pathways that regulate growth and programmed cell death in epithelial cancer cells, with a focus on breast and ovarian cancer. Human epithelial malignancies frequently display deregulated tyrosine kinase activity. Understanding the mechanisms that regulate signaling by these kinases should uncover new ways to inhibit cancer cell growth. 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 fucntion 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010977-02
Application #
7965898
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$612,110
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Schardt, John S; Oubaid, Jinan M; Williams, Sonya C et al. (2017) Engineered Multivalency Enhances Affibody-Based HER3 Inhibition and Downregulation in Cancer Cells. Mol Pharm 14:1047-1056
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
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
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
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
Kales, Stephen C; Ryan, Philip E; Lipkowitz, Stanley (2012) Cbl exposes its RING finger. Nat Struct Mol Biol 19:131-3
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
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
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

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