title: Isoform 5 of PIPKIγ 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 PIPKIγ (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 PIPKIγ (PIPKIγi5) associates with E-cadherin and promotes its lysosomal degradation. Additionally, we show that the endosomal trafficking proteins SNX5 and SNX6 associate with PIPKIγi5 and inhibit PIPKIγi5-mediated E-cadherin degradation. Following HGF stimulation, activated Src directly phosphorylates PIPKIγi5. Phosphorylation of the PIPKIγi5 C-terminus regulates its association with SNX5 and, consequently, E-cadherin degradation. Additionally, this PIPKIγi5-mediated pathway requires Rab7 to promote degradation of internalized E-cadherin. Taken together, the data indicate that PIPKIγi5 and SNX5 are crucial regulators of E-cadherin sorting and degradation. PIPKIγi5, SNX and phosphoinositide regulation of lysosomal sorting represent a novel area of PI(4,5)P2 signaling and research. PIPKIγi5 regulation of E-cadherin sorting for degradation might have broad implications in development and tissue maintenance, and enhanced PIPKIγi5 function might have pathogenic consequences due to downregulation of E-cadherin.
authors.affiliation: Department of Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schill
authors.affiliation: Department of Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hedman
authors.affiliation: Program in Cellular & Molecular Biology, Laboratory of Molecular Biology, University of Wisconsin-Madison, 1525 Linden Drive, Madison, WI 53706, USA.
authors.forename: Suyong
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA raanders@wisc.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D004285:Dogs; D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes; D061985:Madin Darby Canine Kidney Cells; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D015820:Cadherins; D007527:Isoenzymes; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase
keywords: Degradation; E-cadherin; PIPKIγ; SNX5