TY - JOUR
T1 - Oxidative stress decreases phosphatidylinositol 4,5-bisphosphate levels by deactivating phosphatidylinositol-4-phosphate 5-kinase β in a Syk-dependent manner
AU - Chen, Mark Z.
AU - Zhu, Xiaohui
AU - Sun, Hui Qiao
AU - Mao, Yuntao S.
AU - Wei, Yongjie
AU - Yamamoto, Masaya
AU - Yin, Helen L.
PY - 2009/8/28
Y1 - 2009/8/28
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.036509
DO - 10.1074/jbc.M109.036509
M3 - Article
C2 - 19553680
AN - SCOPUS:69949144162
SN - 0021-9258
VL - 284
SP - 23743
EP - 23753
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -