Isoform 5 of PIPKI? regulates the endosomal trafficking and degradation of E-cadherin.

ABSTRACT: Phosphatidylinositol phosphate kinases (PIPKs) have distinct cellular targeting, allowing for site-specific synthesis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] to activate specific signaling cascades required for cellular processes. Several C-terminal splice variants of PIPKI? (also known as PIP5K1C) exist, and have been implicated in a multitude of cellular roles. PI(4,5)P2 serves as a fundamental regulator of E-cadherin transport, and PI(4,5)P2-generating enzymes are important signaling relays in these pathways. We present evidence that the isoform 5 splice variant of PIPKI? (PIPKI?i5) associates with E-cadherin and promotes its lysosomal degradation. Additionally, we show that the endosomal trafficking proteins SNX5 and SNX6 associate with PIPKI?i5 and inhibit PIPKI?i5-mediated E-cadherin degradation. Following HGF stimulation, activated Src directly phosphorylates PIPKI?i5. Phosphorylation of the PIPKI?i5 C-terminus regulates its association with SNX5 and, consequently, E-cadherin degradation. Additionally, this PIPKI?i5-mediated pathway requires Rab7 to promote degradation of internalized E-cadherin. Taken together, the data indicate that PIPKI?i5 and SNX5 are crucial regulators of E-cadherin sorting and degradation. PIPKI?i5, SNX and phosphoinositide regulation of lysosomal sorting represent a novel area of PI(4,5)P2 signaling and research. PIPKI?i5 regulation of E-cadherin sorting for degradation might have broad implications in development and tissue maintenance, and enhanced PIPKI?i5 function might have pathogenic consequences due to downregulation of E-cadherin.

SUBMITTER: Schill NJ 

PROVIDER: S-EPMC4021470 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature