Death-Associated Protein Kinase 1 Phosphorylates Pin1 and Inhibits Its Prolyl Isomerase Activity and Cellular Function

• Published in: Molecular cell 2011-04, Vol.42 (2), p.147-159
• Main Authors: Lee, Tae Ho, Chen, Chun-Hau, Suizu, Futoshi, Huang, Pengyu, Schiene-Fischer, Cordelia, Daum, Sebastian, Zhang, Yan Jessie, Goate, Alison, Chen, Ruey-Hwa, Zhou, Xiao Zhen, Lu, Kun Ping
• Format: Article
• Language: English
• Subjects: active sites; Active Transport, Cell Nucleus; Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; breast neoplasms; Breast Neoplasms - enzymology; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; catalytic activity; Catalytic Domain; Cell Cycle; Cell Nucleus - enzymology; Cell Proliferation; Cell Transformation, Neoplastic - metabolism; Centrosome - metabolism; centrosomes; correlation; Death-Associated Protein Kinases; enzyme activity; Enzyme Stability; Female; HeLa Cells; Humans; Immunohistochemistry; isomerases; Mice; Mice, Knockout; Microscopy, Fluorescence; Mutation; NIH 3T3 Cells; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase - antagonists & inhibitors; Peptidylprolyl Isomerase - genetics; Peptidylprolyl Isomerase - metabolism; Phosphorylation; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Recombinant Fusion Proteins - metabolism; Serine; Signal Transduction; Time Factors; Tissue Array Analysis; Transfection
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.03.005

Pin1 is a phospho-specific prolyl isomerase that regulates numerous key signaling molecules and whose deregulation contributes to disease notably cancer. However, since prolyl isomerases are often believed to be constitutively active, little is known whether and how Pin1 catalytic activity is regulated. Here, we identify death-associated protein kinase 1 (DAPK1), a known tumor suppressor, as a kinase responsible for phosphorylation of Pin1 on Ser71 in the catalytic active site. Such phosphorylation fully inactivates Pin1 catalytic activity and inhibits its nuclear location. Moreover, DAPK1 inhibits the ability of Pin1 to induce centrosome amplification and cell transformation. Finally, Pin1 pSer71 levels are positively correlated with DAPK1 levels and negatively with centrosome amplification in human breast cancer. Thus, phosphorylation of Pin1 Ser71 by DAPK1 inhibits its catalytic activity and cellular function, providing strong evidence for an essential role of the Pin1 enzymatic activity for its cellular function. [Display omitted] ► Pin1 phosphorylation on Ser71 abolishes its catalytic activity and cellular function ► DAPK1 is a kinase responsible for phosphorylation of Pin1 on Ser71 ► DAPK1 inhibits Pin1-induced centrosome amplification and cell transformation ► Pin1 phosphorylation correlates with DAPK1 and centrosome amplification in cancer