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MBC in Press, published online ahead of print February 16, 2005
Mol. Biol. Cell 10.1091/mbc.E04-09-0799

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Submitted on September 13, 2004
Revised on January 24, 2005
Accepted on February 7, 2005

The Type I{alpha} 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,{dagger} Xiang-Ming Zhang,* Susan Luff,* Tony Tiganis,* James C. Whisstock,* Tony Rowe,* Phillip W. Majerus,{dagger} and Christina A. Mitchell*

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

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 PH domain-containing proteins Akt and TAPP-1. Type I{alpha} 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 PtdIns3-P levels and prevented wortmannin-induced endosomal dilatation. Furthermore, mouse embryonic fibroblasts (MEFs) 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 TAPP-1 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 TAPP-1-PH domain membrane recruitment. The 4-phosphatase therefore both generates and terminates PI 3-kinase signals at distinct subcellular locations.

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






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