Kinase-Dependent and -Independent Roles for PTK6 in Colon Cancer

Abstract

Disruption of the gene encoding Protein Tyrosine Kinase 6 (Ptk6) delayed differentiation and increased growth in the mouse intestine. However, Ptk6 null mice were also resistant to azoxymethane-induced colon tumorigenesis. To further explore functions of PTK6 in colon cancer, expression of epithelial and mesenchymal markers, as well as proliferation, migration, and xenograft tumor growth were examined in human colon tumor cell lines with knockdown or overexpression of PTK6. PTK6 protein, transcript, and activation were also examined in a human colon tumor tissue array, using immunohistochemistry (IHC) and qRT-PCR. Knockdown of PTK6 led to the epithelial-mesenchymal transition (EMT) in SW480 and HCT116 cells, while overexpression of PTK6 in SW620 cells restored an epithelial phenotype in a kinase-independent manner. PTK6 knockdown also increased xenograft tumor growth of SW480 cells, suggesting tumor suppressor functions. In clinical specimens, PTK6 expression was highest in normal differentiated epithelial cells and reduced in tumors. In contrast, overexpression of constitutively active PTK6 promoted STAT3 and ERK5 activation in colon cancer cells, and endogenous PTK6 promoted cell survival and oncogenic signaling in response to DNA damaging treatments. These data indicate that PTK6 has complex, context specific functions in colon cancer; PTK6 promotes the epithelial phenotype to antagonize the EMT in a kinase-independent manner, while activation of PTK6 promotes oncogenic signaling.

PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation

“…Interestingly, PTK6 may play a tissue-dependent role in regulating EMT. In contrast to our results with breast epithelial cells and TNBC cells, Mathur and colleagues recently reported that PTK6 promotes the epithelial phenotype in the context of a colon cancer cell line, and PTK6 shRNA expression increased migration, suppressed E-cadherin expression and increased mesenchymal marker expression (49). These seemingly contradictory roles of PTK6 in EMT may be due to tissue-specific contexts, as PTK6 specifically plays a role in the differentiation of colonic epithelial cells (50).…”

Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways

“…The inhibitory role of PTK6 in Wnt signalling raises the idea that the kinase may be downregulated in colorectal carcinogenesis. Indeed, a recent study showed that the level of PTK6 expression was decreased in clinically isolated human colorectal cancers 45 .…”

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

“…PTK6 is a poorly characterized tyrosine kinase, which is amplified or overexpressed in 16% of CRC patients. PTK6 can stimulate CRC cell survival and oncogenic signaling in a kinase dependent manner, but suppresses epithelial-to-mesenchymal transition in a kinase independent fashion 39 . PTK6 rewiring mostly decreased interactions with the CCT chaperonin complex in mtKRAS Hi cells, whereas the interaction with metastasis associated 1 family member 2 (MTA2) was increased (Supplementary Fig.…”