Ubiquitylation of phosphatidylinositol 4-phosphate 5-kinase type I γ by HECTD1 regulates focal adhesion dynamics and cell migration

Xiang Li, Qi Zhou, Manjula Sunkara, Matthew L. Kutys, Zhaofei Wu, Piotr Rychahou, Andrew J. Morris, Haining Zhu, B. Mark Evers, Cai Huang

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Phosphatidylinositol 4-phosphate 5-kinase type Iγ (PIPKIγ90) binds talin and localizes at focal adhesions (FAs). Phosphatidylinositol (4,5)-bisphosphate (PIPγ) generated by PIPKIc90 is essential for FA formation and cell migration. On the other hand, PIPKIγ90 and the b-integrin tail compete for overlapping binding sites on talin. Enhanced PIPKIγ90-talin interaction suppresses talin binding to the bintegrin. It is unknown how PIPKIγ90 is removed from the PIPKIγ90-talin complex after on-site PIP2 production during cell migration. Here we show that PIPKIγ90 is a substrate for HECTD1, an E3 ubiquitin ligase regulating cell migration. HECTD1 ubiquitinated PIPKIγ90 at lysine 97 and resulted in PIPKIγ90 degradation. Expression of the mutant PIPKIc90K97R enhanced PIP2 and PIP3 production, inhibited FA assembly and disassembly and inhibited cancer cell migration, invasion and metastasis. Interestingly, mutation at tryptophan 647 abolished the inhibition of PIPKIγ90K97R on FA dynamics and partially rescued cancer cell migration and invasion. Thus, cycling PIPKIγ90 ubiquitylation by HECTD1 and consequent degradation remove PIPKIγ90 from talin after on-site PIP2 production, providing an essential regulatory mechanism for FA dynamics and cell migration.

Original languageEnglish (US)
Pages (from-to)2617-2628
Number of pages12
JournalJournal of Cell Science
Volume126
Issue number12
DOIs
StatePublished - Jun 2013
Externally publishedYes

Keywords

  • HECTD1
  • Invasion
  • Metastasis
  • PIP5K1C
  • Ubiquitylation

ASJC Scopus subject areas

  • Cell Biology

Fingerprint

Dive into the research topics of 'Ubiquitylation of phosphatidylinositol 4-phosphate 5-kinase type I γ by HECTD1 regulates focal adhesion dynamics and cell migration'. Together they form a unique fingerprint.

Cite this