Abstract
Phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major intracellular signaling mechanism. The phosphorylated Ser/Thr-Pro motifs in a certain subset of phosphoproteins are isomerized specifically by the peptidyl-prolyl cis-trans isomerase Pin1. This post-phosphorylation isomerization can lead to conformational changes in the substrate proteins and modulate their functions. Pin1 interacts with a number of mitotic phosphoproteins, and plays a critical role in mitotic regulation. Recent work indicates that Pin1 is overexpressed in many human cancers and plays an important role in oncogenesis. Pin1 regulates the expression of cyclin D1 by cooperating with Ras signaling and inhibiting the interaction of beta-catenin with the tumor suppressor APC and also directly stabilizing cyclin D1 protein. Furthermore, PIN1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. Pin1 is also a critical regulator of the tumor suppressor p53 during DNA damage response. Given its role in cell growth control and oncogenesis, Pin1 could represent a new anti-cancer target.
Highlights
The phosphorylation of proteins on serine or threonine residues that immediately precede proline residues (Ser/ThrPro) is an important signaling mechanism controlling many cellular processes, such as cell cycle regulation, transcription, cell differentiation and proliferation
Ser/Thr–Pro motifs are the major phosphorylation sites for a large superfamily of ‘proline-directed’ kinases, including cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs) and glycogen synthase kinase 3β (GSK-3β), and they are dephosphorylated by Ser/Thr phosphatases, including PP2A, FCP1 and calcineurin
It has become evident that phosphorylation-dependent prolyl isomerization is a previously uncharacterized postphosphorylation signaling mechanism in cell proliferation and transformation
Summary
Phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major intracellular signaling mechanism. The phosphorylated Ser/Thr-Pro motifs in a certain subset of phosphoproteins are isomerized by the peptidyl-prolyl cis-trans isomerase Pin. The phosphorylated Ser/Thr-Pro motifs in a certain subset of phosphoproteins are isomerized by the peptidyl-prolyl cis-trans isomerase Pin1 This post-phosphorylation isomerization can lead to conformational changes in the substrate proteins and modulate their functions. Pin interacts with a number of mitotic phosphoproteins, and plays a critical role in mitotic regulation. Recent work indicates that Pin is overexpressed in many human cancers and plays an important role in oncogenesis. Pin regulates the expression of cyclin D1 by cooperating with Ras signaling and inhibiting the interaction of β-catenin with the tumor suppressor APC and directly stabilizing cyclin D1 protein. Given its role in cell growth control and oncogenesis, Pin could represent a new anti-cancer target
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