Altered localization and activity of the intracellular tyrosine kinase BRK/Sik in prostate tumor cells

Abstract

Breast tumor kinase (BRK) is an intracellular tyrosine kinase expressed in differentiating epithelial cells of the gastrointestinal tract and skin, and in several epithelial cancers including carcinomas of the breast and colon. We examined expression of BRK and its mouse ortholog Srcrelated intestinal kinase (Sik) in prostate tissues and detected it in the nuclei of normal luminal prostate epithelial cells. BRK localization was then examined in 58 human prostate biopsy samples representing various grades of prostate cancer. While nuclear localization of BRK was present in well-differentiated tumors, it was absent in poorly differentiated tumors. However localization of Sam68, a nuclear substrate of BRK/Sik, was unaltered in all prostate tumors examined. Consistent with these results, nuclear BRK was detected in the more differentiated androgen-responsive LNCaP human prostate cancer cell line that is poorly tumorigenic in host animals, but it was primarily cytoplasmic in the undifferentiated androgen-unresponsive PC3 prostate cancer cell line that forms aggressive tumors. While PC3 cells expressed higher levels of endogenous BRK than LNCaP cells, BRK was less active in these cells. Our data suggest that BRK plays a role in differentiation of prostate epithelial cells. Altered BRK localization and/or activity may provide a prognostic indicator for prostate tumor progression and be a potential target for therapeutic intervention.

PTK (protein tyrosine kinase)-6 and HER2 and 4, but not HER1 and 3 predict long-term survival in breast carcinomas

“…In normal breast epithelium, PTK6 is low or undetectable, but the protein is overexpressed in many breast carcinomas (Petro et al, 2004;Zhang et al, 2005), suggesting, PTK6 expression is related to carcinogenesis. In contrast, high levels of PTK6 are expressed in some differentiating epithelial tissues such as normal gastrointestinal tract, skin (Llor et al, 1999;Haegebarth et al, 2004), and prostate (Derry et al, 2003), and PTK6 expression was associated with the degree of differentiation of breast tissue as indicated by ER expression (Zhao et al, 2003). The correlation of PTK6 protein expression with the histological tumour grade observed in our study may also support an association between PTK6 and cell differentiation.…”

HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

“…[1][2][3][4][5][6] In normal tissues, PTK6 expression is restricted to the differentiated epithelium of the skin and gut, while in tumors the highest levels of PTK6 expression correlate with higher tumor grade, larger size, metastasis, and consequently a poorer prognosis. [7][8][9] PTK6 has specific functions in different tissue types, including regulating differentiation in normal tissues and promoting proliferation and cell survival in tumors, brought about by variations in cellular localization.…”

“…[7][8][9] PTK6 has specific functions in different tissue types, including regulating differentiation in normal tissues and promoting proliferation and cell survival in tumors, brought about by variations in cellular localization. 1,10 PTK6 is activated by a number of different ligands, as well as displaying a small amount of basal auto-phosphorylation in in vitro kinase assays. 11 EGF (epidermal growth factor) and IGF (insulin-like growth factor) induced signaling have been shown to activate PTK6, 9,12,13 as have HGF (hepatocyte growth factor) and osteopontin (OPN).…”

STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation

“…Subsequent characterization of Brk showed it to be present in approximately 60% of human breast tumors, yet absent in normal or fibrocystic mammary tissues. Brk has also been shown to be expressed in other cancer cells, including metastatic melanomas and colon and prostate tumors [6,7,8,9]. However, the molecular mechanism by which Brk participates in tumorigenesis remains poorly characterized.…”