EGF receptor, a member of the ErbB family of receptor tyrosine kinases, plays essential physiological roles in development and mainatenance of epithelial tissues by genrating cell proliferation, survival, differentiation and migration signals in response to specific ligands. Activation of ErbB receptors is linked to etiology of human cancer, including tumor initiation and progression. ErbB receptors also mediate cytoprotection from chemotherapy and radiation, and represent targets for radio- and chemo-sentization of tumors. Elucidating molecular mechanisms that control signaling potency of ErbB receptos is therefore a major goal in cancer biology. Ligand-induced downregulation, representing a balance between lysosomal degradation and recycling to cell sureface, constitutes a major determinant of signaling potency of ErbB receptors. We and others have established that Cbl-family ubiquitin ligase proteins play a crucial role in EGFR down-regulation by faciliatating receptor ubiquitination. The latter is recognized by endosomal ESCRT protein complexes as a signal for lysosomal sorting of the receptor. The precise endocytic step(s) and mechanisms by which Cbl and its closely related, functionally reducndant, family member Cbl-b physiologically operate remain to be established. The biological consequence of negative regulation by Cbl proteins on physiological and oncogenic roles of EGFR also remain to be uncovered. This proposal will utilize unique Cbl/Cbl-b null murine MEF and mammary epithelial cells as wel as Cbl/Cbl-b knockdown human mammary epithelial cells to address whether Cbl proteins selectively control lysosomal sorting of EGFR or if they are also required for initial internalization;reconstitiution of Cbl/Cbl-b deficient cells will provide structural basis for negative regulation of EGFR by Cbl proteins. By using proteomic and gene expression analyses, we will investigate if Cbl proteins provide global or selective regulation of certain signaling modules and link these to biological outputs of EGFR signaling. Finally, we will use mammary gland targeted Cbl/Cbl-b knockout in mice to address the functional consequences of EGFR regulation by Cbl proteins during physiological mammary galnd development and in EGFR-mediated mammary oncogenesis. Insights gained from these studies should further our understanding of receptor tyrosine kinase down-regulation, and may identify newer targets to rationally design anti-cancer agents and to potentiate existing chemotherapeutic and radiation-based cancer cell killing, by countering receptor tyrosine kinase-mediated cytoprotection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA099163-12
Application #
8257171
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
2002-12-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
12
Fiscal Year
2012
Total Cost
$328,717
Indirect Cost
$105,100
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Senanayake, Thulani H; Lu, Yaman; Bohling, Anna et al. (2014) Encapsulation of poorly soluble drugs in polymer-drug conjugates: effect of dual-drug nanoformulations on cancer therapy. Pharm Res 31:1605-15
Rafiq, Khadija; Kolpakov, Mikhail A; Seqqat, Rachid et al. (2014) c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia. Circulation 129:2031-43
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Curran, Jerry; Makara, Michael A; Little, Sean C et al. (2014) EHD3-dependent endosome pathway regulates cardiac membrane excitability and physiology. Circ Res 115:68-78
Helikar, Tomas; Kochi, Naomi; Kowal, Bryan et al. (2013) A comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells. PLoS One 8:e61757
Mohapatra, Bhopal; Ahmad, Gulzar; Nadeau, Scott et al. (2013) Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases. Biochim Biophys Acta 1833:122-39
Zhao, Xiangshan; Mirza, Sameer; Alshareeda, Alaa et al. (2012) Overexpression of a novel cell cycle regulator ecdysoneless in breast cancer: a marker of poor prognosis in HER2/neu-overexpressing breast cancer patients. Breast Cancer Res Treat 134:171-80
Zhao, Xiangshan; Malhotra, Gautam K; Band, Hamid et al. (2012) Derivation of myoepithelial progenitor cells from bipotent mammary stem/progenitor cells. PLoS One 7:e35338
Gudmundsson, Hjalti; Curran, Jerry; Kashef, Farshid et al. (2012) Differential regulation of EHD3 in human and mammalian heart failure. J Mol Cell Cardiol 52:1183-90

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