PTK6 Inhibits Down-regulation of EGF Receptor through Phosphorylation of ARAP1

Abstract

PTK6 (also known as

Protein-tyrosine Phosphatase 1B Antagonized Signaling by Insulin-like Growth Factor-1 Receptor and Kinase BRK/PTK6 in Ovarian Cancer Cells*

“…It sensitizes mammary epithelial cells to EGF (42) and enhances EGF receptor (EGFR) signaling (43,44), and its suppression impairs the signaling response to EGF (45). BRK mediates these effects, at least in part, by inhibiting receptor downregulation, both through phosphorylation of EGFR, which disrupts ubiquitination of the receptor by CBL (46), and by phosphorylation of the BRK-binding protein ARAP1 (47). BRK also affects the function of other EGFR family members.…”

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

“…BRK may contribute to tumorigenesis by modulating EGF/EGFR signaling. It phosphorylates ARAP1, which results sequentially in inhibition of EGFR internalization, increased duration of EGF/EGFR signaling, and increased oncogenic capacity (Kang et al, 2010). Importantly, over-expression of BRK sensitizes human mammary epithelial cells to EGF and/or heregulin stimuli, and increases anchorage-independent growth (Kamalati et al, 1996(Kamalati et al, , 2000, while down-regulation of BRK also influences EGF-and heregulin-induced cell proliferation.…”

“…BRK substrates include RNA-binding proteins (Sam68 (Coyle et al, 2003;Derry et al, 2000;Lukong et al, 2005), SLM-1/2 (Haegebarth et al, 2004), and the polypyrimidine tractbinding protein-associated splicing factor (PSF) (Lukong et al, 2009)), transcription factors (STAT3 (Liu et al, 2006) and STAT5A/B (Weaver and Silva, 2007)), adaptor molecules (STAP-2) (Mitchell et al, 2000), and a variety of signaling molecules (paxillin (Chen et al, 2004), p190RhoGAP (Shen et al, 2008), kinesin-associated protein 3A (KAP3A) (Lukong and Richard, 2008), Akt (Zhang et al, 2005), -catenin (Palka-Hamblin et al, 2010), and ARAP1 (Arf-GAP, Rho-GAP, ankyrin repeat and PH domain-containing protein 1; also known as centaurin δ-2) (Kang et al, 2010)). Although BRK expression is known to induce tyrosine phosphorylation in some of these, similar actions in others have yet to be confirmed.…”

PTK6 (protein tyrosine kinase 6)

“…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 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).…”

“…Overexpression of PTK6 promotes mammary gland cancer tumorigenesis in mouse models (Lofgren et al, 2011;Peng et al, 2013). PTK6 sustains EGFR signaling via transactivation as well as by inhibition of EGFR degradation (Kang et al, 2010;Li et al, 2012). The correlation between PTK6 and ERBB2 overexpression in invasive human ductal breast carcinomas (Born et al, 2005;Aubele et al, 2007;Ostrander et al, 2007;Xiang et al, 2008) raises the possibility that targeting PTK6 along with ERBB receptors might offer a therapeutic advantage (Harvey and Crompton, 2004;Ostrander et al, 2010).…”