TY - JOUR
T1 - Differential Role of MEK5α and MEK5β in BMK1/ERK5 Activation
AU - Cameron, Scott J.
AU - Abe, Jun Ichi
AU - Malik, Sundeep
AU - Che, Wenyi
AU - Yang, Jay
PY - 2004/1/9
Y1 - 2004/1/9
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M308755200
DO - 10.1074/jbc.M308755200
M3 - Article
C2 - 14583600
AN - SCOPUS:0346462989
SN - 0021-9258
VL - 279
SP - 1506
EP - 1512
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 2
ER -