BRK/Sik Tyrosine Kinase Signaling in the Prostate

描述（由申请人提供）：细胞内上皮特异性酪氨酸激酶BRK/Sik属于酪氨酸激酶家族，其成员具有生长抑制功能。BRK/Sik在胃肠道和皮肤的非分裂、分化上皮中表达，我们对BRK/Sik敲除小鼠的研究发现BRK/Sik在结肠中具有潜在的肿瘤抑制功能。相比之下，BRK/Sik在很大比例的乳腺肿瘤中被诱导表达，在这些肿瘤中，BRK/Sik促进生长，其定位主要是细胞质。据报道，不同细胞系统中BRK/Sik的生长抑制和致癌功能明显冲突，这可能是由于其细胞内区隔化的差异。前列腺为解决BRK/Sik细胞内定位在生长控制中的重要性提供了一个杰出的模型。在正常前列腺中，BRK/Sik定位于管腔上皮细胞的细胞核，但在高级别PIN和前列腺肿瘤中，BRK/Sik核定位丢失。我们假设BRK/Sik在定位于细胞核时起肿瘤抑制作用。然而，当BRK/Sik被排除在细胞核外时，它可能促进生长并与一组不同的底物结合。我们将采用互补的体外和体内方法来确定BRK/Sik核定位的意义，我们将检查前列腺细胞系中BRK/Sik调节的信号转导途径。通过基因敲除和转基因小鼠模型，我们将确定BRK/Sik在小鼠前列腺中的作用。初步数据表明，BRK/Sik可能在小鼠前列腺中具有肿瘤抑制功能。前列腺疾病，包括良性前列腺增生（BPH）、前列腺上皮内瘤变（PIN）和前列腺癌，是老年男性最常见的健康问题。我们的数据表明，BRK/Sik的细胞质定位是高级别PIN和前列腺癌的独特标志物。了解由BRK/Sik调控的信号通路可能有助于确定用于治疗前列腺疾病的激酶抑制剂。

DESCRIPTION (provided by applicant): 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.