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

ABSTRACT: Phosphatidylinositol 4-phosphate 5-kinase type I ? (PIPKI?90) binds talin and localizes at focal adhesions (FAs). Phosphatidylinositol (4,5)-bisphosphate (PIP2) generated by PIPKI?90 is essential for FA formation and cell migration. On the other hand, PIPKI?90 and the ?-integrin tail compete for overlapping binding sites on talin. Enhanced PIPKI?90-talin interaction suppresses talin binding to the ?-integrin. It is unknown how PIPKI?90 is removed from the PIPKI?90-talin complex after on-site PIP2 production during cell migration. Here we show that PIPKI?90 is a substrate for HECTD1, an E3 ubiquitin ligase regulating cell migration. HECTD1 ubiquitinated PIPKI?90 at lysine 97 and resulted in PIPKI?90 degradation. Expression of the mutant PIPKI?90(K97R) 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 PIPKI?90(K97R) on FA dynamics and partially rescued cancer cell migration and invasion. Thus, cycling PIPKI?90 ubiquitylation by HECTD1 and consequent degradation remove PIPKI?90 from talin after on-site PIP2 production, providing an essential regulatory mechanism for FA dynamics and cell migration.

SUBMITTER: Li X 

PROVIDER: S-EPMC3687698 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature