Integration of protein kinases mTOR and extracellular signal-regulated kinase 5 in regulating nucleocytoplasmic localization of NFATc4

Teddy T.C. Yang, Raymond Y.L. Yu, Anissa Agadir, Guo Jian Gao, Roberto Campos-Gonzalez, Cathy Tournier, Chi Wing Chow

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The target of rapamycin (TOR) signaling regulates the nucleocytoplasmic shuttling of transcription factors in yeast. Whether the mammalian counterpart of TOR (mTOR) also regulates nucleocytoplasmic shuttling is not known. Using a phospho-specific monoclonal antibody, we demonstrate that mTOR phosphorylates Ser168,170 of endogenous NFATc4, which are conserved gate-keeping Ser residues that control NFAT subcellular distribution. The mTOR acts as a basal kinase during the resting state to maintain NFATc4 in the cytosol. Inactivation and nuclear export of NFATc4 are mediated by rephosphorylation of Ser 168,170, which can be a nuclear event. Kinetic analyses demonstrate that rephosphorylation of Ser168,170 of endogenous NFATc4 is mediated by mTOR and, surprisingly, by extracellular signal-regulated kinase 5 (ERK5) mitogen-activated protein kinase as well. Ablation of ERK5 in the Erk5 -/- cells ascertains defects in NFATc4 rephosphorylation and nucleocytoplasmic shuttling. In addition, phosphorylation of NFATc4 by ERK5 primes subsequent phosphorylation mediated by CK1α. These results demonstrate that distinct protein kinases are integrated to phosphorylate the gate-keeping residues Ser168,170 of NFATc4, to regulate subcellular distribution. These data also expand the repertoire of physiological substrates of mTOR and ERK5.

Original languageEnglish (US)
Pages (from-to)3489-3501
Number of pages13
JournalMolecular and cellular biology
Volume28
Issue number10
DOIs
StatePublished - May 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Yang, T. T. C., Yu, R. Y. L., Agadir, A., Gao, G. J., Campos-Gonzalez, R., Tournier, C., & Chow, C. W. (2008). Integration of protein kinases mTOR and extracellular signal-regulated kinase 5 in regulating nucleocytoplasmic localization of NFATc4. Molecular and cellular biology, 28(10), 3489-3501. https://doi.org/10.1128/MCB.01847-07