VANGL2 protein stability is regulated by integrin ?v and the extracellular matrix.

ABSTRACT: Vang-like 2 (VANGL2) is a four-pass transmembrane protein required for a variety of polarized cell behaviors underlying embryonic development. Recent data show human VANGL2 interacts with integrin ?v to control cell adhesion to extracellular matrix proteins. The goal of this study was to further define the functional relationship between integrin ?v and VANGL2. We demonstrate integrin ?v regulates VANGL2 protein levels both in vitro and in the zebrafish embryo. While integrin ?v knockdown reduces VANGL2 expression at membrane compartments, it does not affect VANGL2 transcription. Knockdown of integrin ?5, but not ?1 or ?3, also decreases VANGL2 protein levels. Inhibition of protein translation using cycloheximide demonstrates that integrin ?v knockdown cells have increased VANGL2 degradation while interference with either proteasome or lysosome function restores VANGL2. We further show integrin activation and stimulation of cell-matrix adhesion using MnCl2 fails to influence VANGL2. However, MnCl2 treatment stabilizes VANGL2 protein expression levels in the presence of cycloheximide. In the converse experiment, blockage of integrin-mediated cell-matrix adhesion using a cyclic RGD peptide causes a reduction in VANGL2 protein levels. Together, our findings support a model where integrin ?v and cellular interactions with the extracellular matrix are required to maintain VANGL2 protein levels and thus function at the plasma membrane.

SUBMITTER: Jessen TN 

PROVIDER: S-EPMC6295236 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature