Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization - PubMed

Affiliations

• PMID: 14504289
• DOI: 10.1074/jbc.M306614200

Free article

Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization

Naoya Fujita et al. J Biol Chem. 2003.

Free article

Abstract

The cyclin-dependent kinase inhibitor p27Kip1 plays an important role in cell cycle regulation. The cyclin-dependent kinase-inhibitory activity of p27Kip1 is regulated by changes in its concentration and its subcellular localization. Several reports suggest that phosphorylation of p27Kip1 at serine 10, threonine 157, and threonine 187 regulate its localization. We have previously identified that carboxyl-terminal threonine 198 (Thr198) in p27Kip1 is a novel phosphorylation site and that Akt is associated with the phosphorylation at the site (Fujita, N., Sato, S., Katayama, K., and Tsuruo, T. (2002) J. Biol. Chem. 277, 28706-28713). We show herein that activation of the Ras/Raf/mitogen-activated protein kinase kinase (MAPK kinase/MEK) pathway also regulates phosphorylation of p27Kip1 at Thr198. MAPKs were not directly associated with p27Kip1 phosphorylation at Thr198, but the p90 ribosomal protein S6 kinases (RSKs) could bind to and directly phosphorylate p27Kip1 at Thr198 in a Ras/Raf/MEK-dependent manner. RSK-dependent phosphorylation promoted the p27Kip1 binding to 14-3-3 and its cytoplasmic localization. To prove the direct relationship between 14-3-3 binding and cytoplasmic localization, we constructed a p27Kip1-R18 fusion protein in which the R18 peptide was fused to the carboxyl-terminal region of p27Kip1. The R18 peptide is known to interact with 14-3-3 independent of phosphorylation. The p27Kip1-R18 distributed mainly in the cytosol, whereas mutant p27Kip1-R18 (p27Kip1-R18-K2) that had no 14-3-3 binding capability existed mainly in the nucleus. These results indicate that RSKs play a crucial role in cell cycle progression through translocation of p27Kip1, in addition to Akt, to the cytoplasm in a phosphorylation and 14-3-3 binding-dependent manner.

Similar articles

• Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization.

  Fujita N, Sato S, Katayama K, Tsuruo T. Fujita N, et al. J Biol Chem. 2002 Aug 9;277(32):28706-13. doi: 10.1074/jbc.M203668200. Epub 2002 May 31. J Biol Chem. 2002. PMID: 12042314

• Cytoplasmic mislocalization of p27Kip1 protein is associated with constitutive phosphorylation of Akt or protein kinase B and poor prognosis in acute myelogenous leukemia.

  Min YH, Cheong JW, Kim JY, Eom JI, Lee ST, Hahn JS, Ko YW, Lee MH. Min YH, et al. Cancer Res. 2004 Aug 1;64(15):5225-31. doi: 10.1158/0008-5472.CAN-04-0174. Cancer Res. 2004. PMID: 15289327

• 14-3-3beta is a p90 ribosomal S6 kinase (RSK) isoform 1-binding protein that negatively regulates RSK kinase activity.

  Cavet ME, Lehoux S, Berk BC. Cavet ME, et al. J Biol Chem. 2003 May 16;278(20):18376-83. doi: 10.1074/jbc.M208475200. Epub 2003 Mar 4. J Biol Chem. 2003. PMID: 12618428

• HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways.

  Le XF, Pruefer F, Bast RC Jr. Le XF, et al. Cell Cycle. 2005 Jan;4(1):87-95. doi: 10.4161/cc.4.1.1360. Epub 2005 Jan 10. Cell Cycle. 2005. PMID: 15611642 Review.

• P90 ribosomal S6 kinases: A bona fide target for novel targeted anticancer therapies?

  Koutsougianni F, Alexopoulou D, Uvez A, Lamprianidou A, Sereti E, Tsimplouli C, Ilkay Armutak E, Dimas K. Koutsougianni F, et al. Biochem Pharmacol. 2023 Apr;210:115488. doi: 10.1016/j.bcp.2023.115488. Epub 2023 Mar 7. Biochem Pharmacol. 2023. PMID: 36889445 Review.

Cited by

• P90 ribosomal S6 kinase confers cancer cell survival by mediating checkpoint kinase 1 degradation in response to glucose stress.

  Ma Y, Cui D, Wang L, Wang Y, Yang F, Pan H, Gong L, Zhang M, Xiong X, Zhao Y. Ma Y, et al. Cancer Sci. 2022 Jan;113(1):132-144. doi: 10.1111/cas.15168. Epub 2021 Nov 3. Cancer Sci. 2022. PMID: 34668620 Free PMC article.

• p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis.

  Theodosakis N, Micevic G, Langdon CG, Ventura A, Means R, Stern DF, Bosenberg MW. Theodosakis N, et al. J Invest Dermatol. 2017 Oct;137(10):2187-2196. doi: 10.1016/j.jid.2016.12.033. Epub 2017 Jun 7. J Invest Dermatol. 2017. PMID: 28599981 Free PMC article.

• SUMOylation regulates p27Kip1 stability and localization in response to TGFβ.

  Lovisa S, Citro S, Sonego M, Dall'Acqua A, Ranzuglia V, Berton S, Colombatti A, Belletti B, Chiocca S, Schiappacassi M, Baldassarre G. Lovisa S, et al. J Mol Cell Biol. 2016 Feb;8(1):17-30. doi: 10.1093/jmcb/mjv056. Epub 2015 Oct 8. J Mol Cell Biol. 2016. PMID: 26450989 Free PMC article.

• Lapatinib resistance in HER2+ cancers: latest findings and new concepts on molecular mechanisms.

  Shi H, Zhang W, Zhi Q, Jiang M. Shi H, et al. Tumour Biol. 2016 Oct 10. doi: 10.1007/s13277-016-5467-2. Online ahead of print. Tumour Biol. 2016. PMID: 27726101 Review.

• Mutant AKT1-E17K is oncogenic in lung epithelial cells.

  De Marco C, Malanga D, Rinaldo N, De Vita F, Scrima M, Lovisa S, Fabris L, Carriero MV, Franco R, Rizzuto A, Baldassarre G, Viglietto G. De Marco C, et al. Oncotarget. 2015 Nov 24;6(37):39634-50. doi: 10.18632/oncotarget.4022. Oncotarget. 2015. PMID: 26053093 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Molecular Biology Databases

  • GlyGen glycoinformatics resource
  • PhosphoSitePlus

• Research Materials

  • NCI CPTC Antibody Characterization Program

• Miscellaneous

  • NCI CPTAC Assay Portal