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doi: 10.1242/10.1242/jcs.00276

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Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer

Akihide Ryo, Yih-Cherng Liou, Kun Ping Lu* and Gerburg Wulf*

Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA



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  		Fig. 1. A novel post-phosphorylation regulatory mechanism in phosphorylation signaling. Phosphorylation of proteins by proline-directed kinases (e.g. CDKs, MAPKs, GSK-3ß) creates binding sites for the prolyl-isomerase Pin1 (1st step). Subsequent prolyl-isomerization by Pin1 induces conformational changes and thereby regulates the function of target proteins (2nd step).

 


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  		Fig. 2. Pin1 functions as a critical catalyst for integrating multiple oncogenic signaling pathways. Pin1 gene expression is induced by growth factor signaling through Neu and Ras signaling. Ras signaling induces JNK/SAPK activity to phosphorylate Jun. Subsequently, Pin1 binds to and isomerizes phosphorylated Jun to enhance its transcriptional activity. In parallel, Pin1 activates the ß-catenin pathway by preventing ß-catenin binding to APC, which can induce Jun gene expression. These signaling cascades eventually lead to an increase in cyclin D1 transcription. Furthermore, Pin1 also directly binds to and stabilizes cyclin D1 protein. In addition, Pin1 can induce the c-Myc gene through the activation of the ß-catenin pathway, which can then enhance cyclin D1 function by inducing Cdk4 gene expression and/or directly activate E2F family genes. Finally, E2F can induce Pin1 expression in a positive feedback loop involving the cyclin D1/E2F pathway.

 




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