Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins

Jeffrey A. Frost, Helge Steen, Paul Shapiro, Tim Lewis, Natalie Ahn, Peter E. Shaw, Melanie H. Cobb

Research output: Contribution to journalArticle

339 Citations (Scopus)

Abstract

Mitogens promote cell growth through integrated signal transduction networks that alter cellular metabolism, gene expression and cytoskeletal organization. Many such signals are propagated through activation of MAP kinase cascades partly regulated by upstream small GTP-binding proteins. Interactions among cascades are suspected but not defined. Here we show that Rho family small G proteins such as Rac1 and Cdc42hs, which activate the JNK/SAPK pathway, cooperate with Raf-1 to activate the ERK pathway. This causes activation of ternary complex factors (TCFs), which regulate c-fos gene expression through the serum response element. Examination of ERK pathway kinases shows that neither MEK1 nor Ras will synergize with Rho-type proteins, and that only MEK1 is fully activated, indicating that MEKs are a focal point for cross-cascade regulation. Rho family proteins utilize PAKs for this effect, as expression of an active PAK1 mutant can substitute for Rho family small G proteins, and expression of an interfering PAK1 mutant blocks Rho-type protein stimulation of ERKs. PAK1 phosphorylates MEK1 on Ser298, a site important for binding of Raf-1 to MEK1 in vivo. Expression of interfering PAK1 also reduces stimulation of TCF function by serum growth factors, while expression of active PAK1 enhances EGF-stimulated MEK1 activity. This demonstrates interaction among MAP kinase pathway elements not previously recognized and suggests an explanation for the cooperative effect of Raf-1 and Rho family proteins on cellular transformation.

Original languageEnglish (US)
Pages (from-to)6426-6438
Number of pages13
JournalEMBO Journal
Volume16
Issue number21
DOIs
StatePublished - 1997

Fingerprint

Ternary Complex Factors
MAP Kinase Signaling System
Chemical activation
Phosphotransferases
Monomeric GTP-Binding Proteins
Gene expression
Proteins
Serum Response Element
fos Genes
Gene Expression
Signal transduction
Mitogen-Activated Protein Kinase Kinases
Cell growth
Mitogens
GTP-Binding Proteins
Epidermal Growth Factor
Metabolism
Signal Transduction
Intercellular Signaling Peptides and Proteins
Binding Sites

Keywords

  • Cross-cascade activation
  • ERK
  • Rho family proteins
  • SRE
  • TCF function

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Frost, J. A., Steen, H., Shapiro, P., Lewis, T., Ahn, N., Shaw, P. E., & Cobb, M. H. (1997). Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO Journal, 16(21), 6426-6438. https://doi.org/10.1093/emboj/16.21.6426

Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. / Frost, Jeffrey A.; Steen, Helge; Shapiro, Paul; Lewis, Tim; Ahn, Natalie; Shaw, Peter E.; Cobb, Melanie H.

In: EMBO Journal, Vol. 16, No. 21, 1997, p. 6426-6438.

Research output: Contribution to journalArticle

Frost, JA, Steen, H, Shapiro, P, Lewis, T, Ahn, N, Shaw, PE & Cobb, MH 1997, 'Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins', EMBO Journal, vol. 16, no. 21, pp. 6426-6438. https://doi.org/10.1093/emboj/16.21.6426
Frost, Jeffrey A. ; Steen, Helge ; Shapiro, Paul ; Lewis, Tim ; Ahn, Natalie ; Shaw, Peter E. ; Cobb, Melanie H. / Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. In: EMBO Journal. 1997 ; Vol. 16, No. 21. pp. 6426-6438.
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