Identification of β-catenin as a target of the intracellular tyrosine kinase PTK6

Abstract

SummaryDisruption of the gene encoding protein tyrosine kinase 6 (PTK6) leads to increased growth, impaired enterocyte differentiation and higher levels of nuclear b-catenin in the mouse small intestine. Here, we demonstrate that PTK6 associates with nuclear and cytoplasmic b-catenin and inhibits b-catenin-and T-cell factor (TCF)-mediated transcription. PTK6 directly phosphorylates b-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64. However, mutation of these sites does not abrogate the ability of PTK6 to inhibit b-catenin transcriptional activity. Outcomes of PTK6-mediated regulation appear to be dependent on its intracellular localization. In the SW620 colorectal adenocarcinoma cell line, nuclear-targeted PTK6 negatively regulates endogenous b-catenin/TCF transcriptional activity, whereas membrane-targeted PTK6 enhances b-catenin/TCF regulated transcription. Levels of TCF4 and the transcriptional co-repressor TLE/Groucho increase in SW620 cells expressing nuclear-targeted PTK6. Knockdown of PTK6 in SW620 cells leads to increased b-catenin/TCF transcriptional activity and increased expression of b-catenin/TCF target genes Myc and Survivin. Ptk6-null BAT-GAL mice, containing a b-catenin-activated LacZ reporter transgene, have increased levels of b-galactosidase expression in the gastrointestinal tract. The ability of PTK6 to negatively regulate b-catenin/TCF transcription by modulating levels of TCF4 and TLE/Groucho could contribute to its growth-inhibitory activities in vivo.

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

“…Importantly, this is associated with a relocalization to the cell membrane, a process that is reported to be essential for PTK6's role in oncogenesis. 36 Finally we show in a large patient cohort (1609 samples) that high PTK6 expression is correlated with reduced metastasisfree survival (Fig. 4A) across all tumor subtypes.…”

Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

“…Accordingly, when HER2 was downregulated, the cell proliferation of JIMT-1 breast cancer cells was also reduced in vivo (9,46). Concerning PTK6 knockdown in vivo only, investigations in the murine small intestine are described and show a contrary role compared with its role in breast cancer (47,48).…”

Interactions of STAP-2 with BRK and STAT3/5 in Breast Cancer Cells

“…BRK also phosphorylates p190RhoGAP-A (regulating the small GTPases, RhoA and Ras, and promoting breast malignancy) (Shen et al, 2008); a kinesin-2 subunit, KAP3A (promoting cell migration) (Lukong and Richard, 2008); and Akt (regulating basal Akt activity in normal cells) (Zhang et al, 2005 Mice deficient in the BRK murine ortholog, Sik, show increased cell proliferation, decreased apoptosis, and increased levels of activated Akt in the small intestine (Haegebarth et al, 2006), suggesting a role for BRK in differentiation of epithelial cells of the small intestine. This is further implied by the evidence that BRK directly phosphorylates and inhibits -catenin, interrupting T-cell factor-mediated transcription in the intestine, and indicating that BRK may be a negative regulator of the Wnt-signaling pathway (Palka-Hamblin et al, 2010). BRK may contribute to tumorigenesis by modulating EGF/EGFR signaling.…”

“…Indeed, oncogenic functions of BRK are enhanced by targeting it to the plasma membrane but are abolished if it is modified to remain in the nucleus (Ie Kim and Lee, 2009). BRK expression is detected in both the cytoplasm and nucleus in the normal intestine, skin and oral epithelium, and in breast and colon tumors (Brauer and Tyner, 2010). In normal differentiated prostate epithelium and in well-differentiated prostate tumors, it is detected in the nucleus, but is absent from the nuclei of poorly-differentiated tumors, which may implicate it in differentiation of the prostate (Derry et al, 2003).…”