Protein tyrosine kinase 6 signaling in prostate cancer

Abstract

More than 25 years have passed since the discovery of protein tyrosine kinase 6 (PTK6), a non-receptor tyrosine kinase distantly related to SRC family kinases. Since then, a variety of data suggest that PTK6 promotes oncogenic signaling and tumorigenesis, generally dependent on its kinase activity. Increased PTK6 expression, activation at the plasma membrane and altered intracellular localization have been discovered in prostate cancers. While PTK6 is localized to nuclei of epithelial cells in normal prostate, it is relocalized and activated at the plasma membrane in prostate tumors. Active PTK6 interacts with and directly phosphorylates AKT, FAK and BCAR1 to promote oncogenic signaling. Furthermore, PTK6 can enhance the epithelial mesenchymal transition by inhibiting E-cadherin expression and inducing expression of the mesenchymal markers vimentin, SLUG and ZEB1. Several lines of evidence suggest that PTK6 plays a role in Pten null prostate tumors. PTEN targets activating phosphorylation of PTK6 and loss of PTEN subsequently leads to PTK6 activation. Different studies provide compelling evidence as to why PTK6 is a potential therapeutic target in prostate cancer. Here, we briefly review the advances and significance of PTK6 in prostate cancer.

Keywords: BRK; PTEN; PTK6; prostate cancer; tyrosine kinase.

Figure 1

PTK6 expression correlates with prostate cancer progression. Analysis of public datasets from NCBI human genome microarray (GEO) website reveals an increase in PTK6 mRNA expression in multiple datasets. A. Primary (N=65) and metastatic prostate tumors (N=25) exhibit higher PTK6 mRNA compared with normal (N=25) and normal adjacent tumor prostate (N=56) (dataset GDS2545 [57], also described in [11]). B. Analysis of dataset GDS4109 [58] indicates that Recurrent (N=40) tumors express higher PTK6 mRNA than non-recurrent prostate tumors (N=39). C. By analyzing dataset GDS1390 [59], we found that patients with androgen independent tumors (N=10) have higher PTK6 mRNA levels than patients with androgen dependent tumors (N=10), suggesting that PTK6 mRNA levels positively correlates with androgen independence. (*) represents P<0.01; (***) represents P<0.001.

Figure 2

Alterations in the PTK6 gene in prostate cancer. Analysis of the cBioPortal database (https://www.cbioportal.org/) indicates that gene alterations in PTK6 occur in prostate cancer. These include both copy number alterations (CNA) and mutations. These datasets correspond to those in Table 1 but differ in number because they represent the percentage of total samples, while Table 1 expresses percentages over total patient number queried for PTK6 gene alterations. Mutations identified include a missense mutation within the kinase domain V315M, and a truncating deletion mutant.