FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2

Yi Tan, John Rouse, Aihua Zhang, Sophia Cariati, Philip Cohen, Michael J. Comb

Research output: Contribution to journalArticle

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Abstract

Fibroblast growth factor (FGF) activates a protein kinase cascade in SK-N-MC cells that regulates gene expression at a cyclic-AMP response element (CRE) by stimulating the transcriptional activity of CREB. The activation of CREB is prevented by a dominant negative mutant of Ras and triggered via the same site (Ser133) that becomes phosphorylated in response to cyclic AMP and Ca2+. However, the effect of FGF is not mediated by cyclic AMP-dependent protein kinase, TPA-sensitive isoforms of protein kinase-C, p70(S6K) or p90(rsk) (all of which phosphorylate CREB at Ser133 in vitro). Instead, we identify the FGF-stimulated CREB kinase as MAP kinase-activated protein (MAPKAP) kinase-2, an enzyme that lies immediately downstream of p38 MAP kinase, in a pathway that is also stimulated by cellular stresses. We show that MAPKAP kinase-2 phosphorylates CREB at Ser133 in vitro, that the FGF- or stress-induced activation of MAPKAP kinase-2 and phosphorylation of CREB and ATF-1 are prevented by similar concentrations of the specific p38 MAP kinase inhibitor SB 203580, and that MAPKAP kinase-2 is the only detectable SB 203580-sensitive CREB kinase in SK-N-MC cell extracts. We also show that transfection of RK/p38 MAP kinase in SK-N-MC cells, but not transfection of p44 MAP kinase, activates Gal4-CREB-dependent transcription via Ser133. These findings identify a new growth factor and stress-activated signaling pathway that regulates gene expression at the CRE.

Original languageEnglish
Pages (from-to)4629-4642
Number of pages14
JournalEMBO Journal
Volume15
Issue number17
Publication statusPublished - 2 Sep 1996

Fingerprint

Fibroblast Growth Factors
Mitogen-Activated Protein Kinase Kinases
p38 Mitogen-Activated Protein Kinases
Cyclic AMP
Phosphotransferases
Response Elements
Gene expression
Transfection
90-kDa Ribosomal Protein S6 Kinases
Chemical activation
Gene Expression
Phosphorylation
Transcription
Cyclic AMP-Dependent Protein Kinases
Cell Extracts
Protein Kinases
Protein Kinase C
Intercellular Signaling Peptides and Proteins
Protein Isoforms
MAP-kinase-activated kinase 2

Keywords

  • CREB transcription
  • FGF
  • Kinase cascade
  • Signaling pathway
  • Stress activation

Cite this

Tan, Yi ; Rouse, John ; Zhang, Aihua ; Cariati, Sophia ; Cohen, Philip ; Comb, Michael J. / FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. In: EMBO Journal. 1996 ; Vol. 15, No. 17. pp. 4629-4642.
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FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. / Tan, Yi; Rouse, John; Zhang, Aihua; Cariati, Sophia; Cohen, Philip; Comb, Michael J.

In: EMBO Journal, Vol. 15, No. 17, 02.09.1996, p. 4629-4642.

Research output: Contribution to journalArticle

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T1 - FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2

AU - Tan, Yi

AU - Rouse, John

AU - Zhang, Aihua

AU - Cariati, Sophia

AU - Cohen, Philip

AU - Comb, Michael J.

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N2 - Fibroblast growth factor (FGF) activates a protein kinase cascade in SK-N-MC cells that regulates gene expression at a cyclic-AMP response element (CRE) by stimulating the transcriptional activity of CREB. The activation of CREB is prevented by a dominant negative mutant of Ras and triggered via the same site (Ser133) that becomes phosphorylated in response to cyclic AMP and Ca2+. However, the effect of FGF is not mediated by cyclic AMP-dependent protein kinase, TPA-sensitive isoforms of protein kinase-C, p70(S6K) or p90(rsk) (all of which phosphorylate CREB at Ser133 in vitro). Instead, we identify the FGF-stimulated CREB kinase as MAP kinase-activated protein (MAPKAP) kinase-2, an enzyme that lies immediately downstream of p38 MAP kinase, in a pathway that is also stimulated by cellular stresses. We show that MAPKAP kinase-2 phosphorylates CREB at Ser133 in vitro, that the FGF- or stress-induced activation of MAPKAP kinase-2 and phosphorylation of CREB and ATF-1 are prevented by similar concentrations of the specific p38 MAP kinase inhibitor SB 203580, and that MAPKAP kinase-2 is the only detectable SB 203580-sensitive CREB kinase in SK-N-MC cell extracts. We also show that transfection of RK/p38 MAP kinase in SK-N-MC cells, but not transfection of p44 MAP kinase, activates Gal4-CREB-dependent transcription via Ser133. These findings identify a new growth factor and stress-activated signaling pathway that regulates gene expression at the CRE.

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