Abstract 3009: Membrane pseudokinase PTK7 regulates metastasis

Studies by others indicate that the membrane pseudokinase 7 (PTK7) regulates canonical and non-canonical Wnt pathways and controls orientation of cells in a tissue plane (planar cell polarity, PCP). There is still no clear understanding of the PTK7 role in cancer: Is it pro-tumorigenic or anti-tumorigenic? Our live cell imaging and cell invasion studies suggest that full-length PTK7 expressed in HT1080 fibrosarcoma cells inhibits directed cell motility, lamellipodia polarization and cell invasion. Using the fluorescence imaging we demonstrated that the expression of full-length PTK7 in HT1080-RFP cells in nude mice significantly reduces lung colonization (metastasis). The pro-invasive membrane type-1 matrix metalloprotease (MT1-MMP/MMP-14) coupled with an ADAM/ADAMTS family member(s) directly cleave PTK7 at the cell surface and reverse the inhibitory anti-invasive signal of full-length PTK7. Ectodomain proteolysis was a prerequisite for the intramembrane cleavage of the residual fragments of PTK7 by γ-secretase. The resulting C-terminal PTK7 fragment translocated to the cell nucleus. To identify the molecular mechanisms downstream of PTK7 proteolysis, we used genome-wide transcriptional profiling and kinome analysis. Full-length PTK7 and the PTK7 mutants representing the cleaved PTK7 forms differentially regulated the expression of multiple genes and induced signaling pathways associated with cell movement, Wnt signaling and cancer. We believe that the regulation of PTK7 proteolysis opens new possibilities to control Wnt signaling, cancer cell invasion and metastasis. Citation Format: Vladislav Golubkov, Yong Zhang, Natalie Prigozhina, Robert M. Hoffman, Alex Strongin. Membrane pseudokinase PTK7 regulates metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3009. doi:10.1158/1538-7445.AM2014-3009