Differential Role of MEK5α and MEK5β in BMK1/ERK5 Activation

Scott J. Cameron, Jun Ichi Abe, Sundeep Malik, Wenyi Che, Jay Yang

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Big mitogen-activated protein kinase 1/extracellular-regulated kinase 5 (BMK1/ERK5) is regulated sequentially by a series of upstream MAP kinase kinases (MEKs) in a signaling cascade. MEKs activate their downstream MAPK by phosphorylation of threonine and tyrosine in the T-X-Y motif. MEK5 is the upstream BMK1 kinase and exists as naturally occurring splice variants, MEK5α and MEK5β. The full-length MEK5 (MEK5α) is 89 amino acids longer than MEK5β at the N terminus, but the precise functional difference between the two splice variants is not known. Dual phosphorylation site mutation of MEK5α (Ser-311 → Asp and Thr-315 → Asp; MEK5α(S311D/T315D)) activated BMK1, but the corresponding dual phosphorylation sites mutant of MEK5β could not induce BMK1 kinase activation or nuclear translocation. Furthermore, MEK5β inhibited epidermal growth factor-induced BMK1 activation and MEK5α (S311D/T315D)-induced MEF2 transcriptional activity. Both MEK5α and MEK5β individually co-immunoprecipitated with BMK1, but the presence of MEK5β prevented association of MEK5α with BMK1 suggesting a mechanistic basis for the dominant-negative behavior of MEK5β on BMK1 activation. The ratio of MEK5α to MEK5β expression was higher in cancer cell lines, and overexpression of MEK5β-inhibited serum-induced DNA synthesis. These data suggest that alternative splicing of MEK5α and MEK5β may play a critical role in BMK1 activation and subsequent cell proliferation.

Original languageEnglish (US)
Pages (from-to)1506-1512
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number2
DOIs
StatePublished - Jan 9 2004

Fingerprint

Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 7
Phosphorylation
Phosphotransferases
Chemical activation
Mitogen-Activated Protein Kinase Kinases
Alternative Splicing
Threonine
Epidermal Growth Factor
Tyrosine
Cell proliferation
Cell Proliferation
Amino Acids
Cell Line
Mutation
DNA
Cells
Association reactions
Serum
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Differential Role of MEK5α and MEK5β in BMK1/ERK5 Activation. / Cameron, Scott J.; Abe, Jun Ichi; Malik, Sundeep; Che, Wenyi; Yang, Jay.

In: Journal of Biological Chemistry, Vol. 279, No. 2, 09.01.2004, p. 1506-1512.

Research output: Contribution to journalArticle

Cameron, Scott J. ; Abe, Jun Ichi ; Malik, Sundeep ; Che, Wenyi ; Yang, Jay. / Differential Role of MEK5α and MEK5β in BMK1/ERK5 Activation. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 2. pp. 1506-1512.
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