Prolyl isomerase, Pin1: new findings of post-translational modifications and physiological substrates in cancer, asthma and Alzheimer’s disease

Abstract

The peptidyl prolyl cis/trans isomerase Pin1 specifically binds phosphorylated Ser/Thr-Pro protein motifs and catalyzes the cis/trans isomerization of the peptide bond. Accumulating studies have revealed that Pin1 isomerase activity is regulated by its post-translational modifications, including phosphorylation and oxidation. Various transcription factors and regulators have been identified as substrates for Pin1. It enhances AP-1 activity via isomerization of both c-Jun and c-Fos for cellular proliferation and stabilizes the oncosuppressors p53 and p73 against DNA damage at the checkpoint. We demonstrated the association between the intracellular form of Notch1 (NIC) and Pin1 by analyzing Pin1/p53 double-knockout mice. Pin1 also regulates the post-transcriptional level of some cytokines, associated with asthma, that possess 3' untranslated region AU-rich elements (AREs) via interaction withAUF1, the nucleoprotein in the ARE-binding complex. Pin1 has been identified as the molecular partner of tau and amyloid precursor protein (APP), the key factors of Alzheimer's disease (AD). It interacts with the phosphorylated Thr-231 of tau and regulates its activity to bind microtubules. It further interacts with the phosphorylated Thr-668 of APP and affects its metabolism. Thus, Pin1 is probably involved in the pathogenesis of human diseases, including cancer, asthma, and AD, presenting an attractive target for future therapeutical drugs.

Novel Role of Pin1 Induction in Type II Collagen-Mediated Rheumatoid Arthritis

“…Thus, MAPKs are not required for Pin1-mediated COX-2 expression. Abnormal Pin1 activity contributes to the pathogenesis of diverse diseases, including cancer, Alzheimer's disease, asthma, and allergies (24,46,47). We show in this study for the first time that Pin1 may also be a suitable target for RA.…”

Endoplasmic reticulum stress or mutation of an EF-hand Ca2+-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis

“…Beyond playing a role in the appropriate folding of nascent proteins, some PPIase proteins play a role in signal transduction by facilitating protein conversion to active protein conformations. The PIN1 PPIase facilitates isomerization of only phosphorlyated-Ser/Thr-Pro motifs on substrate proteins, regulating a wide array of cellular functions including gene expression, cell division, and stress response (Butterfield et al 2006;Lu and Zhou 2007;Rudrabhatla and Pant 2010;Takahashi et al 2007). The FKBP52/HSP90 complex binds to cytoplasmic glucocorticoid receptors, enhancing receptor affinity for steroid ligand and facilitating interaction between the bound receptor and dynein during receptor translocation to the nucleus (Davies and Sanchez 2005).…”

Pin1 Associates with and Induces Translocation of CRTC2 to the Cytosol, Thereby Suppressing cAMP-responsive Element Transcriptional Activity*

“…tified as Pin1 substrates, including p53, cyclin D1, and Tau (2)(3)(4)(5). Pin1 interacts with a number of target proteins through recognition of phospho-Ser/Pro motifs, and the proline conformational change induced by Pin1 modifies the structures and functions, such as stabilization, phosphorylation, and translocation, of target proteins (4 -7).…”