title: TPA-induced cell transformation provokes a complex formation between Pin1 and 90 kDa ribosomal protein S6 kinase 2.
abstract: Post-translational modification of peptidyl cis/trans prolyl isomerase Pin1 is crucial in regulation of gene stability. Pin1 phosphorylation at Ser(16) has been regarded as a marker for Pin1 isomerase activity and introduction of phosphorylation on Ser/Thr-Pro of substrate proteins is prerequisite for its binding activity with Pin1 and subsequent isomerization. Here, we found that 90 kDa ribosomal protein S6 kinase 2 (RSK2) could form a physical complex with Pin1, leading to phosphorylation of Pin1 at Ser(16) ex vivo and in vitro respectively. Intriguingly, Pin1(+/+) mouse embryonic fibroblasts (MEFs) exhibited significantly an increase in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced RSK2 phosphorylation with a marginal Pin1 phosphorylation compared with Pin1(-/-) MEFs. Moreover, TPA-induced Ser(16) Pin1 phosphorylation as well as RSK2 phosphorylation was considerably profound in RSK(+/+) MEFs but not in RSK(-/-) MEFs. Consequently, knockdown of Pin1 using shRNA-Pin1 suppressed TPA-induced cell transformation in JB6 CI41 cells. Overall, these results indicate that Pin1 plays a critical role in TPA-induced tumorigenesis plausibly via physical interaction with RSK2 and reciprocal phosphorylation, therefore suggesting a potential therapeutic target for cancer treatment.
authors.affiliation: Department of Pharmacy, Keimyung University, Dalseo-gu, Taegu, Republic of Korea.
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
authors.forename: Seung Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Sang-Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Kee-Min
authors.initials: KM
authors.lastname: Woo
authors.forename: Kyung-Ae
authors.initials: KA
authors.lastname: Lee
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000737:chemistry / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D013755:Tetradecanoylphorbol Acetate