title: VANGL2 regulates membrane trafficking of MMP14 to control cell polarity and migration.
abstract: Planar cell polarity (PCP) describes the polarized orientation of cells within the plane of a tissue. Unlike epithelial PCP, the mechanisms underlying PCP signaling in migrating cells remain undefined. Here, the establishment of PCP must be coordinated with dynamic changes in cell adhesion and extracellular matrix (ECM) organization. During gastrulation, the membrane type-1 matrix metalloproteinase (MT1-MMP or MMP14) is required for PCP and convergence and extension cell movements. We report that the PCP protein Vang-like 2 (VANGL2) regulates the endocytosis and cell-surface availability of MMP14 in manner that is dependent on focal adhesion kinase. We demonstrate that zebrafish trilobite/vangl2 mutant embryos exhibit increased Mmp14 activity and decreased ECM. Furthermore, in vivo knockdown of Mmp14 partially rescues the Vangl2 loss-of-function convergence and extension phenotype. This study identifies a mechanism linking VANGL2 with MMP14 trafficking and suggests that establishment of PCP in migrating gastrula cells requires regulated proteolytic degradation or remodeling of the ECM. Our findings implicate matrix metalloproteinases as downstream effectors of PCP and suggest a broadly applicable mechanism whereby VANGL2 affects diverse morphogenetic processes.
authors.affiliation: Division of Genetic Medicine/Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232,  USA.
authors.forename: B Blairanne
authors.initials: BB
authors.lastname: Williams
authors.forename: V Ashley
authors.initials: VA
authors.lastname: Cantrell
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Mundell
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Bennett
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Quick
authors.forename: Jason R
authors.initials: JR
authors.lastname: Jessen
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D004625:Embryo, Nonmammalian; D004705:Endocytosis / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D005775:Gastrula / Q000196:embryology / Q000378:metabolism*; D054262:Gastrulation / Q000235:genetics*; D055785:Gene Knockdown Techniques; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D021381:Protein Transport / Q000502:physiology; D059748:Proteolysis; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D029961:Zebrafish Proteins; C491759:vangl2 protein, zebrafish; D051416:Focal Adhesion Protein-Tyrosine Kinases; D053511:Matrix Metalloproteinase 14