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There are two human histidine acid phosphatases: prostatic (PAP, ACPP) and lysosomal (LAP, ACP2). PAP is additionally a tyrosine phosphatase, linked with the growth-suppressing effect of PAP. Its expression is absent or decreased in prostate cancer tissue. Precise knowledge of the function of PAP is lacking. To study the function of PAP, active site modeling and mice lacking the activity of PAP were generated. We show that PAP dephosphorylates effectively the lipid second messenger, phosphatidylinositol-3-phosphate [PI(3)P]. Interacting residues are only conserved among PAP but not among LAP and PAP/PI(3)P interaction is similar to the interaction of E.coli phytase/phytate. The removal of PAP activity caused adenocarcinoma of the prostate, and surprisingly, myopathy and neuropathy. Proliferation is increased and apoptosis is decreased possibly due to inactivating GSK3beta phosphorylation. Signaling defects are a common disease mechanism and our results clearly assign PAP to PI(3)P-signaling.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]