Oxidative stress decreases phosphatidylinositol 4,5-bisphosphate levels by deactivating phosphatidylinositol-4-phosphate 5-kinase β in a Syk-dependent manner

Mark Z. Chen, Xiaohui Zhu, Hui Qiao Sun, Yuntao S. Mao, Yongjie Wei, Masaya Yamamoto, Helen L. Yin

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2) has many essential functions and its homeostasis is highly regulated. We previously found that hypertonic stress increases PIP2 by selectively activating the β isoform of the type I phosphatidylinositol phosphate 5-kinase (PIP5Kβ) through Ser/Thr dephosphorylation and promoting its translocation to the plasma membrane. Here we report that hydrogen peroxide (H2O2) also induces PIP5Kβ Ser/Thr dephosphorylation, but it has the opposite effect on PIP2 homeostasis, PIP5Kβ function, and the actin cytoskeleton. Brief H2O2 treatments decrease cellular PIP2 in a PIP5Kβ-dependent manner. PIP5Kβ is tyrosine phosphorylated, dissociates from the plasma membrane, and has decreased lipid kinase activity. In contrast, the other two PIP5K isoforms are not inhibited by H2O2. We identified spleen tyrosine kinase (Syk), which is activated by oxidants, as a candidate PIP5Kβ kinase in this pathway, and mapped the oxidant-sensitive tyrosine phosphorylation site to residue 105. The PIP5KβY105E phosphomimetic is catalytically inactive and cytosolic, whereas the Y105F non-phosphorylatable mutant has higher intrinsic lipid kinase activity and is much more membrane associated than wild type PIP5Kβ. These results suggest that during oxidative stress, as modeled by H2O2 treatment, Syk-dependent tyrosine phosphorylation of PIP5Kβ is the dominant post-translational modification that is responsible for the decrease in cellular PIP2.

Original languageEnglish (US)
Pages (from-to)23743-23753
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number35
DOIs
StatePublished - Aug 28 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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