PTPA Regulating PP2A as a Dual Specificity Phosphatase

Abstract

There are multiple regulatory devices of protein phosphatase type 2A (PP2A), known on the biochemical level: association of regulatory subunits, interaction with other proteins, covalent modification by phosphorylation on tyrosyl and threonine residues, methylation of the carboxy terminus (see ref. 1 for a recent review). In this chapter still another device will be described and discussed. Although PP2A is generally known as a phosphatase that specifically dephosphorylates seryl and threonyl residues, it can also operate as a phosphotyrosyl phosphatase, and this activity can be regulated independently. Historically, PP2A was the first phosphatase described that could remove phosphate from phosphotyrosyl residues (2,3) and is, therefore, a “dual specificity” phosphatase “avant la lettre.” The in vitro characterization of the dual specificity of PP2A indicated that the phosphoseryl and phosphotyrosyl phosphatase activities exhibited distinct catalytic properties and thermostability (2,4); they were either conversely affected by free ATP or pyrophosphate (5), or concurrently stimulated by tubulin (6). Further observations led to the isolation of a protein that specifically stimulates the phosphotyrosyl phosphatase activity of PP2A without affecting its Ser-P/Thr-P phosphatase activity (3,7–9). This phosphotyrosyl phosphatase activator or PTPA was shown to be highly specific for the dimeric form of PP2A (PP2A_D) (7). PTPA stimulates the PTPase activity of PP2A_D in a time-dependent enzyme-like reaction requiring ATP, Mg²⁺ as essential cofactor that cannot ble ATP analogs (7).be replaced by nonhydrolysa