Mixed-lineage kinase 3 phosphorylates prolyl-isomerase Pin1 to regulate its nuclear translocation and cellular function. Journal Article


Authors: Rangasamy, V.; Mishra, R.; Sondarva, G.; Das, S; Lee, T. H.; Bakowska, J. C.; Tzivion, G.; Malter, J. S.; Rana, B.; Lu, K. P.; Kanthasamy, A.; Rana, A.
Article Title: Mixed-lineage kinase 3 phosphorylates prolyl-isomerase Pin1 to regulate its nuclear translocation and cellular function.
Abstract: Nuclear protein peptidyl-prolyl isomerase Pin1-mediated prolyl isomerization is an essential and novel regulatory mechanism for protein phosphorylation. Therefore, tight regulation of Pin1 localization and catalytic activity is crucial for its normal nuclear functions. Pin1 is commonly dysregulated during oncogenesis and likely contributes to these pathologies; however, the mechanism(s) by which Pin1 catalytic activity and nuclear localization are increased is unknown. Here we demonstrate that mixed-lineage kinase 3 (MLK3), a MAP3K family member, phosphorylates Pin1 on a Ser138 site to increase its catalytic activity and nuclear translocation. This phosphorylation event drives the cell cycle and promotes cyclin D1 stability and centrosome amplification. Notably, Pin1 pSer138 is significantly up-regulated in breast tumors and is localized in the nucleus. These findings collectively suggest that the MLK3-Pin1 signaling cascade plays a critical role in regulating the cell cycle, centrosome numbers, and oncogenesis.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 109
Issue: 21
ISSN: 1091-6490; 0027-8424
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 8149
End Page: 8154
Language: English
DOI/URL:
Notes: ID: 12479; Record Owner: From MEDLINE, a database of the U.S. National Library of Medicine.; Status: MEDLINE; Publishing Model: Journal available in: Print-Electronic Citation processed from: Internet; NLM Journal Code: pv3, 7505876; Other ID: Source: NLM. PMC3361382; CAS Registry/EC Number/Name of Substance: 0 (CCND1 protein, human). 0 (NIMA-interacting peptidylprolyl isomerase). 136601-57-5 (Cyclin D1). 147336-22-9 (Green Fluorescent Proteins). 56-45-1 (Serine). EC 2-7-11-25 (MAP Kinase Kinase Kinases). EC 2-7-11-25 (mitogen-activated protein kinase kinase kinase 11). EC 5-2-1-8 (Peptidylprolyl Isomerase).; Grant Number: R01 GM55835 (United States NIGMS NIH HHS), R01 NS074443 (United States NINDS NIH HHS); Electronic Date of Publication: 20120507; Entry Date: 20120802