The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases

doi:10.1073/pnas.0509740102

The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases

^*Division of Hematology, Washington University School of Medicine, St. Louis, MO 63110; and ^‡Institute for Animal Health, Compton, Berkshire RG20 7NN, United Kingdom

Contributed by Philip W. Majerus, November 9, 2005

Abstract

Numerous inositol polyphosphate 5-phosphatases catalyze the degradation of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P₂) to phosphatidylinositol-4-phosphate (PtdIns-4-P). An alternative pathway to degrade PtdIns-4,5-P₂ is the hydrolysis of PtdIns-4,5-P₂ by a 4-phosphatase, leading to the production of PtdIns-5-P. Whereas the bacterial IpgD enzyme is known to catalyze this reaction, no such mammalian enzyme has been found. We have identified and characterized two previously undescribed human enzymes, PtdIns-4,5-P₂ 4-phosphatase type I and type II, which catalyze the hydrolysis of PtdIns-4,5-P₂ to phosphatidylinositol-5-phosphate (PtdIns-5-P). Both enzymes are ubiquitously expressed and localize to late endosomal/lysosomal membranes in epithelial cells. Overexpression of either enzyme in HeLa cells increases EGF-receptor degradation upon EGF stimulation.

Footnotes

↵ § To whom correspondence should be addressed. E-mail: phil{at}im.wustl.edu.
↵ † A.U. and C.H. contributed equally to this work.
Author contributions: A.U., M.W., and P.W.M. designed research; A.U., C.H., M.K., S.-C.C., J.Z., Y.F., and M.W. performed research; E.E.G. contributed new reagents/analytic tools; C.H., M.K., and P.W.M. analyzed data; and A.U., C.H., S.-C.C., M.W., and P.W.M. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations: EEA1, early endosomal antigen 1; EGFR, EGF receptor; PtdIns-4,5-P₂, phosphatidylinositol-4,5-bisphosphate; PtdIns-5-P, phosphatidylinositol-5-phosphate; PtdIns-3,5-P₂, phosphatidylinositol-3,5-bisphosphate; PtdIns-4,5-P₂ 4-Ptase I, PtdIns-4,5-P₂ 4-phosphatase type I; PtdIns-4,5-P₂ 4-Ptase II, PtdIns-4,5-P₂ 4-phosphatase type II; siRNA, small interfering RNA.
↵ ¶ This work was presented at the 60th Harden Conference on inositol phosphates and lipids, August 13, 2005.