COT phosphorylates prolyl-isomerase Pin1 to promote tumorigenesis in breast cancer.

摘要: Pin1, a conserved eukaryotic Peptidyl-prolyl cis/trans isomerase, has profound effects on numerous key-signaling molecules, and its deregulation contributes to disease, particularly cancer. Although Pin1-mediated prolyl isomerization is an essential novel regulatory mechanism for protein phosphorylation, little known about the upstream signaling pathway(s) that regulates Pin1 activity. Here, we identify MAP3K-related serine-threonine kinase (the gene encoding COT/Tpl2) as responsible phosphorylation of Ser16. COT interacts with phosphorylates Consequently, Ser16 by increases cyclin D1 abundance enhances tumorigenecity MCF7 cells. In contrast, depletion in cells leads downregulation which subsequently decrease levels, inhibiting xenograft model, treatment TKI, inhibitor, Juglone, abrogates tumor growth. human breast cancer patients, immunohistochemical staining shows pSer16 levels are positively correlated providing strong evidence role COT/Pin1 axis conveying oncogenic signals promote aggressiveness