PTK6 (protein tyrosine kinase 6)

Description	Isoform 1 Size: 451 amino acids; ~ 52 KDa. PTK6 contains SH3 and SH2 protein-protein interaction domains, an SH1 kinase domain, and a regulatory carboxy terminus. Phosphorylation of residue Y342 is required for full activation of kinase activity and activity is negatively regulated by tyrosine phosphorylation of its carboxy-terminal tyrosine residue, Y-447 (Qiu and Miller, 2002; Qiu and Miller, 2004; Qiu et al., 2005). Isoform 2 (also known as ALT-PTK6, delta m5) Size: 134 aa; ~15 KDa. ALT-PTK6 is the product of an alternatively-spliced RNA that encodes a truncated protein due to a premature stop codon; alternative splicing deletes exon 2 and causes in a frameshift. The N-terminus and SH3 domain of ALT-PTK6 are identical to the full-length protein, but it has a unique C-terminus lacking the SH2 and SH1 domains and is thus catalytically inactive (Mitchell et al., 1994; Brauer et al., 2011). Two additional PTK6 sequences, CRA_a (GenBank: EAW75262.1) and CRA_b (GenBank: EAW75263.1) that would encode larger ~59 kDa proteins have been identified by Celera Genomics, but these isoforms have not been characterized and their biological significance is not known.
Expression	Normal Epithelium PTK6 was first identified in cultured human melanocytes (Lee et al., 1993), breast tumor cells (Mitchell et al., 1994), and mouse small intestine (Siyanova et al., 1994). It is primarily an epithelial kinase that is first detectable in the differentiating granular layer of the skin during late embryogenesis of the mouse at E15.5 (Vasioukhin et al., 1995). In adults, PTK6 is predominantly expressed in the epithelial cells of the gastrointestinal tract (Siyanova et al., 1994; Llor et al., 1999), and skin (Vasioukhin et al., 1995; Wang et al., 2005). In regenerating tissues, such as the small intestine, colon, and skin, PTK6 expression is largely restricted to epithelial cells that are exiting the cell cycle and undergoing terminal differentiation, which are located on the villi in the small intestine, surface epithelium in the colon (Haegebarth et al., 2006), and the suprabasal layer of the skin (Vasioukhin et al., 1995; Wang et al., 2005) as well as in the oral mucosa (Petro et al., 2004). PTK6 is also expressed in the nuclei of normal epithelium of the prostate (Derry et al., 2003), and mammary gland (Peng et al., 2014). Although it is largely restricted to epithelia, PTK6 expression was also reported in activated normal T-cells (Kasprzycka et al., 2006). 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-1a and HIF-2a (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 been identified as a transcriptional target of CREB, and its expression is upregulated by p90RSK2 phosphorylation of CREB (Jin et al., 2013). PTK6 expression is modestly upregulated in primary colon tumors (Llor et al., 1999), and downregulated in metastatic colon cancer (Chen et al., 1999). In squamous cell carcinoma, PTK6 expression is reduced with increasing malignancy (Petro et al., 2004; Wang et al., 2005).
Function	PTK6 is an intracellular protein tyrosine kinase that has distinct context-dependent functions in different normal and cancerous tissues based on its intracellular localization and kinase activity. Studies in breast and ovarian cancer cell lines find that PTK6 interacts with growth factor receptors EGFR (Kamalati et al., 2000) and ERBB2 (Ostrander et al., 2007; Xiang et al., 2008) to propagate growth factor-mediated signaling. PTK6 binds and phosphorylates IGF-1R (Fan et al., 2013) and promotes anchorage independent growth via interactions with IRS-4 and IGF1R (Qiu et al., 2005; Irie et al., 2010). PTK6 has also been shown to mediate Met receptor signaling, although a direct interaction has not been demonstrated (Locatelli et al., 2012). PTK6 stabilizes EGFR expression by phosphorylating ARAP1 (Arf-GAP, Rho-GAP, ankyrin repeat, and pleckstrin homology domain-containing protein 1) (Kang et al., 2010); interaction with EGFR mediates PTK6 phosphorylation of paxillin (Chen et al., 2004) and p190RhoGAP (Shen et al., 2008) in breast cancer cells as well as AKT in breast (Zhang et al., 2005) and prostate (Zheng et al., 2010) cancer cell lines to promote proliferation, invasion, and migration. 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 pro-oncogenic 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). β-catenin has also been identified as a PTK6 substrate; when targeted to the cell membrane PTK6 can activate β-catenin, while nuclear PTK6 negatively regulates β-catenin transcriptional activity in a kinase-independent manner (Palka-Hamblin et al., 2010). PTK6 phosphorylation of the nuclear RNA-splicing factors SAM68 (Derry et al., 2000) and related SLM1 and SLM2 proteins (Haegebarth et al., 2004), as well as PSF (Lukong et al., 2009) inhibits their RNA-binding activity to promote differentiation and cell cycle arrest. PTK6 is a substrate of the PTP1B phosphatase (Fan et al., 2013). PTK6 promotes epithelial differentiation of enterocytes in the small intestine (Haegebarth et al., 2006) and keratinocytes in skin (Vasioukhin and Tyner, 1997; Wang et al., 2005). In cultured human keratinocytes, addition of calcium promotes differentiation, which is accompanied by increased PTK6 expression and activation, and elevated levels of the epidermal differentiation markers (Vasioukhin and Tyner, 1997) dependent on PTK6 kinase activity (Wang et al., 2005). Disruption of the Ptk6 gene led to impaired intestinal differentiation and increased intestinal proliferation in mice (Haegebarth et al., 2006). When ectopically expressed, PTK6 sensitized non-transformed Rat1a fibroblasts to apoptosis (Haegebarth et al., 2005). Induction of PTK6 in intestinal crypts following total body γ-irradiation enhanced apoptosis in the murine intestinal epithelium, including in intestinal crypts, where it promotes DNA damage-induced apoptosis (Haegebarth et al., 2009). In human colon cancer cell lines and in murine colon tissue, PTK6 negatively regulates β-catenin transcriptional activity (Palka-Hamblin et al., 2010). PTK6 has a tumor-promoting role in the colon as disruption of the Ptk6 gene impaired carcinogen-induced tumorigenesis in mice (Gierut et al., 2011) and PTK6 promotes survival of colon cancer cell lines following DNA damaging treatments including γ-irradiation and chemotherapeutic drugs via STAT3 activation (Gierut et al., 2012). Targeting PTK6 to plasma membrane enhanced proliferation, survival, migration and anchorage-independent growth in HEK293 cells, while nuclear targeting inhibited the invasive phenotype (Kim and Lee, 2009). Targeting active PTK6 to the plasma membrane in SYF (deficient for SRC, YES, and FYN) mouse embryonic fibroblasts was sufficient to transform these cells (Zheng et al., 2013a). In prostate cancer cells, targeting PTK6 to the nucleus inhibits proliferation while cytoplasmic PTK6 promotes proliferation (Brauer et al., 2010). Overexpression of membrane-targeted active PTK6 in prostate cancer cells drives epithelial-mesenchymal 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 human prostate and breast cancers, PTK6 is activated at the plasma membrane (Zheng et al., 2013b; Peng et al., 2014).

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