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DA-Raf, a dominant-negative regulator of the Ras-ERK pathway, is essential for skeletal myocyte differentiation including myoblast fusion and apoptosis
- Source :
- Experimental cell research. 376(2)
- Publication Year :
- 2018
-
Abstract
- Ras-activated ERK pathway (Raf-MEK-ERK phosphorylation cascade) regulates a variety of cellular responses including cell proliferation, differentiation, survival, and apoptosis. DA-Raf1 (DA-Raf) is a splicing variant of A-Raf and contains the Ras-binding domain but lacks the kinase domain. Accordingly, DA-Raf antagonizes the Ras-ERK pathway in a dominant-negative manner. Here we show that DA-Raf plays essential roles in skeletal myocyte differentiation including myoblast fusion and in apoptosis, which are suppressed by the Ras-ERK pathway. Expression of DA-Raf was highly induced in C2C12 skeletal myocytes in a low serum concentration of differentiation condition and in NIH3T3 fibroblasts under a serum starvation apoptosis-inducing condition. Stable knockdown of DA-Raf resulted in suppression of muscle-specific gene expression, myoblast fusion, and apoptosis. In contrast, exogenous overexpression of DA-Raf prominently caused apoptosis. DA-Raf induces apoptosis by preventing ERK-RSK-mediated inhibitory phosphorylation of Bad. Although it has been reported that apoptosis triggers myoblast fusion, DA-Raf-induced apoptosis was not involved in myoblast fusion in C2C12 cells. These results imply that suppression of the Ras-ERK pathway by DA-Raf is essential for both myocyte differentiation including myoblast fusion and apoptosis but that apoptosis is not a prerequisite for myoblast fusion.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
MAP Kinase Signaling System
Muscle Fibers, Skeletal
Apoptosis
Biology
Proto-Oncogene Proteins A-raf
Phosphorylation cascade
Cell Line
Cell Fusion
03 medical and health sciences
Myoblast fusion
Mice
0302 clinical medicine
Skeletal muscle cell differentiation
Myocyte
Animals
Humans
Cell Differentiation
Cell Biology
musculoskeletal system
Cell biology
030104 developmental biology
HEK293 Cells
030220 oncology & carcinogenesis
NIH 3T3 Cells
ras Proteins
Phosphorylation
C2C12
Subjects
Details
- ISSN :
- 10902422
- Volume :
- 376
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Experimental cell research
- Accession number :
- edsair.doi.dedup.....d226329bd52eec6439a741e688a3e312