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Vol. 16, Issue 5, 2218-2233, May 2005

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The Type I Inositol Polyphosphate 4-Phosphatase Generates and Terminates Phosphoinositide 3-Kinase Signals on Endosomes and the Plasma Membrane

Ivan Ivetac ^*, Adam D. Munday ^*, Marina V. Kisseleva , Xiang-Ming Zhang ^*, Susan Luff ^*, Tony Tiganis ^*, James C. Whisstock ^*, Tony Rowe ^*, Phillip W. Majerus , and Christina A. Mitchell ^*

^* Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia 3800; Department of Hematology, Washington University Medical School, St. Louis, MO 63130

Submitted September 13, 2004; Revised January 24, 2005; Accepted February 7, 2005
Monitoring Editor: Jean Gruenberg

Endosomal trafficking is regulated by the recruitment of effector proteins to phosphatidylinositol 3-phosphate [PtdIns(3)P] on early endosomes. At the plasma membrane, phosphatidylinositol-(3,4)-bisphosphate [PtdIns(3,4)P₂] binds the pleckstrin homology (PH) domain-containing proteins Akt and TAPP1. Type I inositol polyphosphate 4-phosphatase (4-phosphatase) dephosphorylates PtdIns(3,4)P₂, forming PtdIns(3)P, but its subcellular localization is unknown. We report here in quiescent cells, the 4-phosphatase colocalized with early and recycling endosomes. On growth factor stimulation, 4-phosphatase endosomal localization persisted, but in addition the 4-phosphatase localized at the plasma membrane. Overexpression of the 4-phosphatase in serum-stimulated cells increased cellular PtdIns(3)P levels and prevented wortmannin-induced endosomal dilatation. Furthermore, mouse embryonic fibroblasts from homozygous Weeble mice, which have a mutation in the type I 4-phosphatase, exhibited dilated early endosomes. 4-Phosphatase translocation to the plasma membrane upon growth factor stimulation inhibited the recruitment of the TAPP1 PH domain. The 4-phosphatase contains C2 domains, which bound PtdIns(3,4)P₂, and C2-domain-deletion mutants lost PtdIns(3,4)P₂ 4-phosphatase activity, did not localize to endosomes or inhibit TAPP1 PH domain membrane recruitment. The 4-phosphatase therefore both generates and terminates phosphoinositide 3-kinase signals at distinct subcellular locations.

Abbreviations used: EEA, early endosomal antigen; 4-phosphatase, inositol polyphosphate 4-phosphatase; 5-phosphatase, inositol polyphosphate 5-phosphatase; MTOC, microtubule organizing center; PtdIns(3,4)P₂, phosphatidylinositol (3,4)-bisphosphate; PtdIns3-P, phosphatidylinositol 3-phosphate; PI 3-kinase, phosphoinositide 3-kinase; PM, plasma membrane; TAPP1, tandem PH domain-containing protein-1.

Address correspondence to: Christina A. Mitchell (christina.mitchell{at}med.monash.edu.au).

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