Send to

Choose Destination
See comment in PubMed Commons below
Bone. 2009 Jan;44(1):53-60. doi: 10.1016/j.bone.2008.09.013. Epub 2008 Oct 7.

Arkadia represses the expression of myoblast differentiation markers through degradation of Ski and the Ski-bound Smad complex in C2C12 myoblasts.

Author information

Division of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Ariake, Tokyo, Japan.


The differentiation of myoblasts is regulated by multiple extracellular and intracellular factors. Of the extracellular regulators, members of transforming growth factor-beta (TGF-beta) family play critical roles in the regulation of osteoblasts and myoblast differentiation. Little is known, however, about the regulation of Myostatin/TGF-beta signaling during myoblast differentiation. In this study, we examined the roles of Arkadia, an E3 ubiquitin ligase, in Myostatin/TGF-beta signaling and the regulation of myoblast differentiation. Knockdown of Arkadia reduced Myostatin/TGF-beta signaling and enhanced the differentiation of C2C12 myoblasts. In addition, exogenous overexpression of Arkadia enhanced Myostatin/TGF-beta signaling, preventing myoblast differentiation. In the absence of the activation of Myostatin/TGF-beta signaling, knockdown of Arkadia enhanced myoblast differentiation via upregulation of Ski protein, an intracellular enhancer of myoblast differentiation. Arkadia likely affected the differentiation of myoblasts in a Smad-independent fashion by inducing Ski degradation. Knockdown of Arkadia increased the Myostatin-induced phosphorylation of Smad2/3 in C2C12 cells. Arkadia bound Smad2/3 via Ski to induce the ubiquitination of Smad2/3. These results suggest that Arkadia targets Ski-bound, inactive phospho-Smad2/3 to regulate positively Myostatin/TGF-beta signaling. Taken together, this study indicates that Arkadia regulates myoblast differentiation through both Smad-dependent and Smad-independent pathways.

[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center