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.
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Velusamy
authors.initials: V
authors.lastname: Rangasamy
authors.forename: Rajakishore
authors.initials: R
authors.lastname: Mishra
authors.forename: Gautam
authors.initials: G
authors.lastname: Sondarva
authors.forename: Subhasis
authors.initials: S
authors.lastname: Das
authors.forename: Tae Ho
authors.initials: TH
authors.lastname: Lee
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Bakowska
authors.forename: Guri
authors.initials: G
authors.lastname: Tzivion
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
authors.forename: Basabi
authors.initials: B
authors.lastname: Rana
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
authors.forename: Anumantha
authors.initials: A
authors.lastname: Kanthasamy
authors.forename: Ajay
authors.initials: A
authors.lastname: Rana
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D002453:Cell Cycle / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D019938:Cyclin D1; D049452:Green Fluorescent Proteins; D020930:MAP Kinase Kinase Kinases; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D012694:Serine; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C530104:CCND1 protein, human; C000606846:PIN1 protein, human