Uncoupling Raf1 from MEK1/2 impairs only a subset of cellular responses to Raf activation

G. Pearson, R. Bumeister, D. O. Henry, M. H. Cobb, M. A. White

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Abstract

The Raf family of serine/threonine protein kinases is intimately involved in the transmission of cell regulatory signals controlling proliferation and differentiation. The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. However, accumulating evidence suggests that there are additional Raf substrates and that subsets of Raf-induced regulatory events are mediated independently of Raf activation of MEK1/2. To examine the possibility that there is bifurcation at the level of Raf in activation of MEK1/2-dependent and MEK1/2-in-dependent cell regulatory events, we engineered a kinase-active Raf1 variant (RafBXB(T481A)) with an amino acid substitution that disrupts MEK1 binding. We find that disruption of MEK1/2 association uncouples Raf from activation of ERK1/2, induction of serum-response element-dependent gene expression, and induction of growth and morphological transformation. However, activation of NF-κB-dependent gene expression and induction of neurite differentiation were unimpaired. In addition, Raf-dependent activation of p90 ribosomal S6 kinase was only slightly impaired. These results support the hypothesis that Raf kinases utilize multiple downstream effectors to regulate distinct cellular activities.

Original languageEnglish (US)
Pages (from-to)37303-37306
Number of pages4
JournalJournal of Biological Chemistry
Volume275
Issue number48
DOIs
StatePublished - Dec 1 2000

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90-kDa Ribosomal Protein S6 Kinases
Serum Response Element
raf Kinases
Chemical activation
Gene Expression
Protein-Serine-Threonine Kinases
Neurites
Amino Acid Substitution
Phosphotransferases
Gene expression
Growth
Proteins
Substrates
Substitution reactions
Association reactions
Amino Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Uncoupling Raf1 from MEK1/2 impairs only a subset of cellular responses to Raf activation. / Pearson, G.; Bumeister, R.; Henry, D. O.; Cobb, M. H.; White, M. A.

In: Journal of Biological Chemistry, Vol. 275, No. 48, 01.12.2000, p. 37303-37306.

Research output: Contribution to journalArticle

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