BRK tyrosine kinase expression in a high proportion of human breast carcinomas

Barker, Karen; Jackson, Laura E.; Crompton, M. R.

doi:10.1038/sj.onc.1201241

Cited by 153 publications

(147 citation statements)

References 18 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Ikeda

Miyasaka

Sekine

et al. 2009

Biochemical and Biophysical Research Communications

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Signal transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains Pleckstrin and Src homology 2 (SH2)-like domains as well as a YXXQ motif in its C-terminal region. STAP-2 is also known as breast tumor kinase (Brk) substrate (BKS). Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation.Importantly, small-interfering RNA-mediated reduction of endogenous STAP-2 expression decreased Brk-mediated STAT3 activation. Taken together, our findings demonstrate that STAP-2 is phosphorylated at Tyr250 by Brk, and plays an important role in Brk-mediated STAT3 activation.3

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Section: Introductionmentioning

confidence: 99%

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

Ikeda

Miyasaka

Sekine

et al. 2009

Biochemical and Biophysical Research Communications

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“…The cytoplasmic non-receptor tyrosine kinase (BRK, PTK6), originally cloned from a human metastatic breast tumour (Mitchell et al, 1994), shows elevated expression in breast carcinoma cell lines and in approximately two-thirds of primary breast tumours (Mitchell et al, 1994;Barker et al, 1997;Llor et al, 1999;Born et al, 2005). Overexpression of PTK6-mRNA positively correlates with hormone receptor status (Zhao et al, 2003) and HER2/NEU expression (Born et al, 2005) in breast cancer specimens.…”

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confidence: 99%

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

et al. 2007

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The HER receptors are of therapeutic and prognostic significance in breast cancer, and their function is modulated by cytoplasmic tyrosine kinases like PTK6 (brk). We performed a retrospective study on archival breast cancer samples from patients with long follow-up and compared the protein expression between individual HERs and between HERs and the PTK6. Univariate and multivariate analyses were used to study the prognostic value of parameters. Metastases-free survival of patients for longer than 240 months was inversely associated (Pp0.05) with nodal status, tumour size, and oestrogen receptor status, but was also directly associated with high protein expression levels of HER4 and PTK6 in Kaplan -Meier analysis. In multivariate analysis for metastases-free survival of 4240 months, the stepwise selected parameters were tumour size (relative risk 3.1), PTK6 expression (0.4), and number of positive lymph nodes (1.2). Furthermore, we demonstrated a timedependence of the prognostic value attributed to the parameters. The HER receptors (HER2,4), but not PTK6, were independent prognostic markers for metastases-free survival at 60 months, whereas at 240 months PTK6 is the strongest prognostic marker. We demonstrate that PTK6 is a prognostic marker of metastases-free survival in breast cancer, and is independent of the classical morphological and molecular markers of lymph node involvement, tumour size, and HER2 status.

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“…BRK is expressed in many breast carcinoma cell lines and in a high percentage of primary breast tumors that have been examined, but it has not been detected in normal human breast tissue (Mitchell et al, 1994;Barker et al, 1997), or at any stage of mammary gland differentiation in the mouse (Llor et al, 1999). BRK was also cloned from cultured human melanocytes and designated PTK6 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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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.

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BRK tyrosine kinase expression in a high proportion of human breast carcinomas

Cited by 153 publications

References 18 publications

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

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

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

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

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