DA-Raf, a dominant-negative regulator of the Ras-ERK pathway, is essential for skeletal myocyte differentiation including myoblast fusion and apoptosis.
Exp Cell Res
; 376(2): 168-180, 2019 03 15.
Article
in En
| MEDLINE
| ID: mdl-30742807
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Differentiation
/
Muscle Fibers, Skeletal
/
MAP Kinase Signaling System
/
Proto-Oncogene Proteins A-raf
Limits:
Animals
/
Humans
Language:
En
Journal:
Exp Cell Res
Year:
2019
Document type:
Article
Affiliation country:
Japan