Abstract 1496: Proteolytic regulation of the Wnt/PCP pathway in cancer

The non-canonical Wnt signaling pathway regulates planar cell polarity (PCP) and directed cell motility in processes as diverse as embryogenesis and cancer cell invasion. Here, we establish that the protein tyrosine kinase-7 (PTK7), an essential component of the Wnt/PCP pathway, strongly inhibits cancer cell invasion by reorganizing the actin cytoskeleton and altering actomyosin contraction. We also demonstrate that the pro-invasive membrane type-1 matrix metalloproteinase (MT1-MMP) functions as a principal sheddase of PTK7 and reverses its inhibition of cell invasion. MT1-MMP directly cleaves the PKP621↓LI sequence localized in an exposed region of the seventh Ig-like domain, generating an N-terminal, soluble PTK7 species (sPTK7) that interacts with membrane PTK7 in a dominant-negative fashion. Protease activity was reciprocally correlated with levels of PTK7 in several cell types and during zebrafish embryogenesis. Reduced PTK7 levels were observed in breast tumours compared to normal breast tissue. Conceptually, our data suggest that the Wnt/PCP pathway converges with pericellular proteolysis to regulate cell motility in normal development and cancer. Further insight into MT1-MMP regulation of Wnt/PCP may promote understanding of directional cell motility in embryogenesis and cancer and lead to identification of therapeutics to treat PCP-related developmental disorders and malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1496. doi:10.1158/1538-7445.AM2011-1496