Our efforts to identify genes that regulate intestinal epithelial cell differentiation led to the discovery of Brk (Breast tumor kinase, also called PTK6 and Sik). Brk is a non-myristoylated, intracellular epithelial-specific tyrosine kinase that is expressed in breast tumors where it has been proposed to contribute to oncogenic signaling. However we discovered that Brk is expressed at highest levels in the normal intestine, where it is localized to nondividing, differentiated epithelial cells. To elucidate functions of Brk in vivo, we disrupted the mouse Brk gene, and found that loss of Brk enhanced growth and delayed enterocyte differentiation in the small intestine. In addition, we discovered that Brk is induced in intestinal epithelial crypt cells in response to ?-irradiation. We detected impaired apoptosis in the Brk-/- mouse after total body irradiation, indicating that induction of Brk in the crypts contributes to apoptosis. In addition our preliminary data suggest that Brk-/- mice are more susceptible to the colon carcinogen azoxymethane than wild type mice. We hypothesize that Brk regulates intestinal tissue homeostasis, and acts as a tumor suppressor in the intestinal tract, in contrast to its role in breast cancer. To define the roles of Brk in regulation of growth, differentiation, and apoptosis in intestinal epithelial cells, we propose: 1) To determine if Brk regulates growth and apoptosis by negatively regulating Akt using engineered cell lines, and wild type and Brk-deficient mice. In preliminary studies, we detected increased activation of Akt, a key positive regulator of growth and survival signaling and a substrate of Brk in intestines of Brk- /- mice;2) To explore mechanisms underlying the ability of Brk to regulate differentiation of intestinal epithelial cells, using novel cell culture and animal models, and 3) To evaluate contributions of Brk to tumorigenesis in the intestine. We will determine if Brk has tumor suppressor functions using a variety of different mouse colon cancer model systems and engineered cell lines. Our data suggest that Brk has different functions in normal intestine and in breast cancer, which may be dependent on its intracellular localization and access to different signaling molecules within the cell. Our studies are directed at determining the normal physiological functions of the Brk tyrosine kinase, which will be important for understanding its potential contributions to intestinal tissue homeostasis and the development of intestinal cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044525-17
Application #
8050174
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Hamilton, Frank A
Project Start
1993-05-01
Project End
2012-03-31
Budget Start
2011-02-01
Budget End
2012-03-31
Support Year
17
Fiscal Year
2011
Total Cost
$305,198
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Mathur, Priya S; Gierut, Jessica J; Guzman, Grace et al. (2016) Kinase-Dependent and -Independent Roles for PTK6 in Colon Cancer. Mol Cancer Res 14:563-73
Hart, Peter C; Ratti, Bianca A; Mao, Mao et al. (2016) Caveolin-1 regulates cancer cell metabolism via scavenging Nrf2 and suppressing MnSOD-driven glycolysis. Oncotarget 7:308-22
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Patel, Priyank; Asbach, Benedikt; Shteyn, Elina et al. (2015) Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4. Mol Cell Biol 35:1506-22
Chastkofsky, Michael I; Bie, Wenjun; Ball-Kell, Susan M et al. (2015) Protein Tyrosine Kinase 6 Regulates UVB-Induced Signaling and Tumorigenesis in Mouse Skin. J Invest Dermatol 135:2492-2501
Peng, Maoyu; Emmadi, Rajyasree; Wang, Zebin et al. (2014) PTK6/BRK is expressed in the normal mammary gland and activated at the plasma membrane in breast tumors. Oncotarget 5:6038-48
Wang, Zebin; Zheng, Yu; Park, Hyun Jung et al. (2013) Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma. Mol Cancer Ther 12:759-67
Zheng, Yu; Tyner, Angela L (2013) Context-specific protein tyrosine kinase 6 (PTK6) signalling in prostate cancer. Eur J Clin Invest 43:397-404
Zheng, Yu; Wang, Zebin; Bie, Wenjun et al. (2013) PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer. Cancer Res 73:5426-37
Peng, M; Ball-Kell, S M; Franks, R R et al. (2013) Protein tyrosine kinase 6 regulates mammary gland tumorigenesis in mouse models. Oncogenesis 2:e81

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