The intracellular epithelial-specific tyrosine kinase BRK/Sik belongs to a tyrosine kinase family whose members have growth inhibitory functions. BRK/Sik is expressed in nondividing, differentiating epithelial linings of the gastrointestinal tract and skin, and our studies in BRK/Sik knockout mice have revealed a potential tumor suppressor function for BRK/Sik in the colon. In contrast, BRK/Sik expression is induced in a high percentage of breast tumors where it promotes growth and its localization is predominantly cytoplasmic. The apparent conflicting growth suppressor and oncogenic functions reported for BRK/Sik in different cell systems may be due to differences in its intracellular compartmentalization. The prostate provides an outstanding model for addressing the significance of BRK/Sik intracellular localization in growth control. In the normal prostate, BRK/Sik is localized to nuclei of luminal epithelial cells, but BRK/Sik nuclear localization is lost in high-grade PIN and in prostate tumors. We hypothesize that BRK/Sik acts a tumor suppressor when localized to the nucleus. However, BRK/Sik may facilitate growth and associate with a different set of substrates when excluded from the nucleus. We will use complementary in vitro and in vivo approaches to determine the significance of BRK/Sik nuclear localization, and we will examine BRK/Sik regulated signal transduction pathways in prostate cell lines. Using knockout and transgenic mouse models, we will determine the role of BRK/Sik in the mouse prostate. Preliminary data suggest that BRK/Sik may have tumor suppressor functions in the mouse prostate. Disorders of the prostate, including benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and prostate cancer, are among the most common health problems of older men. Our data suggest that cytoplasmic localization of BRK/Sik is a unique marker for high-grade PIN and prostate cancer. Understanding signaling pathways regulated by BRK/Sik may lead to the identification of kinase inhibitors to be used therapeutically to treat prostate disorders.
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