Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins

The reversible protein phosphorylation on serine or threonine residues that precede proline (pSer/Thr-Pro) is a key signaling mechanism for the contro l of various cellular processes, including cell division. The pSer/Thr-Pro moiety in peptides exists in the two completely distinct cia and trans conf ormations whose conversion is catalyzed specifically by the essential proly l isomerase Pin1. Previous results suggest that Pin1 might regulate the con formation and dephosphorylation of its substrates. However, it is not known whether phosphorylation-dependent prolyl isomerization occurs in a native protein and/or affects dephosphorylation of pSer/Thr-Pro motifs. Here we sh ow that the major Pro-directed phosphatase PP2A is conformation-specific an d effectively dephosphorylates only the trans pSer/Thr-Pro isomer. Furtherm ore, Pin1 catalyzes prolyl isomerization of specific pSer/Thr-Pro motifs bo th in Cdc25C and tau to facilitate their dephosphorylation by PP2A. Moreove r, Pin1 and PP2A show reciprocal genetic interactions, and prolyl isomerase activity of Pin1 is essential for cell division in vivo. Thus, phosphoryla tion-specific prolyl isomerization catalyzed by Pin1 is a novel mechanism e ssential for regulating dephosphorylation of certain pSer/Thr-Pro motifs.