Building a better understanding of the intracellular tyrosine kinase PTK6 — BRK by BRK

Abstract

Protein tyrosine kinase 6 (PTK6), also referred to as breast tumor kinase BRK, is a member of a distinct family of kinases that is evolutionarily related to the SRC family of tyrosine kinases. While not expressed in the normal mammary gland, PTK6 expression is detected in a large proportion of human mammary gland tumors. In breast tumor cells, PTK6 promotes growth factor signaling and cell migration. PTK6 expression is also increased in a number of other epithelial tumors, including ovarian and colon cancer. In contrast, PTK6 is expressed in diverse normal epithelia, including the linings of the gastrointestinal tract, skin and prostate, where its expression correlates with cell cycle exit and differentiation. Disruption of the mouse Ptk6 gene leads to increased growth and impaired differentiation in the small intestine that is accompanied by increased AKT and Wnt signaling. Following total body irradiation, PTK6 expression is induced in proliferating progenitor cells of the intestine, where it plays an essential role in DNA-damage induced apoptosis. A distinguishing feature of PTK6 is its flexibility in intracellular localization, due to a lack of amino-terminal myristoylation/ palmitoylation. Recently a number of substrates of PTK6 have been identified, including nuclear RNA-binding proteins and transcription factors. We discuss PTK6 signaling, its apparent conflicting roles in cancer and normal epithelia, and its potential as a therapeutic target in epithelial cancers.

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

“…5,27 However, the lack of commercially available specific inhibitors has not allowed for further investigations. Our in vitro results in both breast and colorectal cell line models show that PTK6 induction in hypoxia can be regulated by HIF-independent mechanisms, such as posttranslational modifications.…”

“…25 Furthermore, PTK6 has been reported to regulate a number of processes that are central for cellular proliferation and metastatic spread, when associated with different membrane subcellular fractions. 26,27 The subcellular localization of normoxic and hypoxic PTK6 was investigated by biochemical and immunofluorescence approaches, where a clear increase in cytoplasmic hypoxic PTK6 was observed (Fig. S3).…”

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

“…A wide variety of biological functions are regulated by BRK (30,31). In normal cells, it has been implicated in the control of differentiation and apoptosis; in contrast, in cancer cells BRK has been reported to enhance mitogenic signals and cell proliferation, protect breast cancer cells from anchorage-independent autophagic cell death, and promote migration and invasion (31,41).…”

“…BRK/PTK6 is a member of a family of PTKs that bear structural similarity to SRC (30,31). Although both feature SH2, SH3, and PTK domains, there are differences in the regulatory roles of these domains between BRK and SRC (30,31).…”

“…Although both feature SH2, SH3, and PTK domains, there are differences in the regulatory roles of these domains between BRK and SRC (30,31). BRK activity is regulated by autophosphorylation, with the SH2 and SH3 domains serving in an autoinhibitory capacity (32).…”