Isoform 5 of PIPKIγ regulates the endosomal trafficking and degradation of E-cadherin

Nicholas J. Schill, Andrew C. Hedman, Suyong Choi, Richard A. Anderson

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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 Ecadherin degradation. Following HGF stimulation, activated Src directly phosphorylates PIPKIγi5. Phosphorylation of the PIPKIγi5 Cterminus regulates its association with SNX5 and, consequently, Ecadherin 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 PIPKIci5 function might have pathogenic consequences due to downregulation of E-cadherin.

Original languageEnglish (US)
Pages (from-to)2189-2203
Number of pages15
JournalJournal of cell science
Volume127
Issue number10
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Degradation
  • E-cadherin
  • PIPKIγ
  • SNX5

ASJC Scopus subject areas

  • Cell Biology

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