Protein-tyrosine Kinase 6 Promotes Peripheral Adhesion Complex Formation and Cell Migration by Phosphorylating p130 CRK-associated Substrate

Abstract

Background: Protein-tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase that is aberrantly expressed in several types of human cancer. Results: PTK6 directly phosphorylates p130 CRK-associated substrate (p130CAS). Conclusion: PTK6 promotes peripheral adhesion complex formation and prostate cancer cell migration by phosphorylating p130CAS and activating ERK5. Significance: These studies define a novel PTK6-p130CAS-ERK5 signaling cascade in cancer cells.

Brk/Protein Tyrosine Kinase 6 Phosphorylates p27KIP1, Regulating the Activity of Cyclin D–Cyclin-Dependent Kinase 4

“…Brk lacks the amino-terminal myristoylation/palmitoylation typical of Src family members and, as such, has a wider area of localization and binding partners (44)(45)(46). Several Brk substrates have been identified (24), including ␤-catenin, p190RhoGAP, Paxillin, PSF, STAT3, Sam68, SLM1, SLM2, AKT, p130CAS, and FAK (47), but the identification of p27 as a direct phosphorylation target provides new insights about Brk's role in proliferation control and directly links it to cdk regulation. Others have suggested that Brk has additional roles in p27 regulation: in MDA MB 231 cells and Src, Yes, and Fyn null mouse embryonic fibroblast (MEFs), Brk overexpression transcriptionally downregulates p27 (47,48).…”

PTK6 (protein tyrosine kinase 6)

“…Cancer PTK6 is overexpressed in a large majority of human breast tumors and in most breast cancer cell lines (Barker et al, 1997;Harvey and Crompton, 2003;Ostrander et al, 2007). PTK6 expression is also induced in prostate tumors and cell lines (Zheng et al, 2012); relocalization of PTK6 from the nucleus to cytoplasm was reported in prostate cancer cells (Derry et al, 2003). In breast cancer cells, PTK6 expression has been shown to be mediated by hypoxia via multiple mechanisms; PTK6 protein is stabilized by HSP90 (Kang et al, 2012) and is transcriptionally upregulated by HIF-1α and HIF-2α (Regan Anderson et al, 2013), additionally PTK6 protein can be upregulated in a post-translational manner in response to hypoxia (Pires et al, 2014).…”

“…PTK6 has also been shown to promote breast cancer cell migration via phosphorylation of KAP3A (Lukong and Richard, 2008) and Dok1 (Miah et al, 2014). Membrane-targeted active PTK6 in prostate cancer cell lines phosphorylates prooncogenic substrates BCAR1 (Zheng et al, 2012) and FAK (Zheng et al, 2013a). PTK6 phosphorylates and activates Signal Transducers and Activators of Transcription STAT3 (Liu et al, 2006) and STAT5a (Weaver and Silva, 2007) as well as the related scaffolding protein STAP2 (Mitchell et al, 2000).…”

“…In prostate cancer cells, targeting PTK6 to the nucleus inhibits proliferation while cytoplasmic PTK6 promotes proliferation . Overexpression of membrane-targeted active PTK6 in prostate cancer cells drives epithelialmesenchymal transition (Zheng et al, 2012) and anchorage-independent survival (Zheng et al, 2013a) as well as in vivo xenograft metastasis (Zheng et al, 2013b). Recently, PTK6 was detected in nuclei of normal mammary gland epithelium (Peng et al, 2014), and overexpression of PTK6 promotes oncogenic signaling and invasive phenotypes in breast cancer cells (Harvey and Crompton, 2003;Xiang et al, 2008;Irie et al, 2010).…”

“…In the cytoplasm, PTK6 may phosphorylate AKT on tyrosine residues to promote activation and downstream signaling . Targeting active PTK6 to the plasma membrane in prostate cancer cells drives epithelialmesenchymal transition via activation of BCAR1 (Zheng et al, 2012) and anchorage-independent survival via activation of FAK (Zheng et al, 2013a). RSK-mediated expression of PTK6 may contribute to metastasis of prostate cancer cells (Yu et al, 2014).…”