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Molecular and Cellular Biology, August 2009, p. 4130-4143, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00199-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cdo Binds Abl To Promote p38{alpha}/β Mitogen-Activated Protein Kinase Activity and Myogenic Differentiation{triangledown}

Gyu-Un Bae,1,2 Bok-Geon Kim,2 Hye-Jin Lee,2 Ji-Eun Oh,2 Su-Jae Lee,3 Wei Zhang,1,{dagger} Robert S. Krauss,1* and Jong-Sun Kang2*

Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York 10029,1 Samsung Biomedical Research Institute, SungKyunKwan University School of Medicine, Suwon 440-746, South Korea,2 Department of Chemistry, Hanyang University, Seoul 133-791, South Korea3

Received 12 February 2009/ Returned for modification 16 March 2009/ Accepted 14 May 2009

The p38 mitogen-activated protein kinase (MAPK) pathway is required for differentiation of skeletal myoblasts, but how the pathway is activated during this process is not well understood. One mechanism involves the cell surface receptor Cdo (also known as Cdon), which binds to Bnip-2 and JLP, scaffold proteins for Cdc42 and p38, respectively; formation of these complexes results in Bnip-2/Cdc42-dependent activation of p38. It has been reported that the tyrosine kinase Abl promotes myogenic differentiation in a manner dependent on its cytoplasmic localization, but the cytoplasmic signaling proteins with which it interacts to achieve this effect are unidentified. We report that Abl associates with both Cdo and JLP during myoblast differentiation. Abl binds a proline-rich motif in Cdo via its SH3 domain, and these regions of Abl and Cdo are required for their promyogenic effects. Cdo is important for full Abl kinase activity, and Abl is necessary for full activation of p38 MAPK, during myogenic differentiation. As seen with myoblasts depleted of Cdo, the diminished differentiation displayed by Abl-depleted cells is rescued by the expression of an activated form of the immediate upstream p38-activating kinase MAPK kinase 6. Abl's promyogenic effect is therefore linked to a multiprotein cell surface complex that regulates differentiation-dependent p38 activation.

* Corresponding author. Mailing address for Robert S. Krauss: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029. Phone: (212) 241-2177. Fax: (212) 860-9279. E-mail: Robert.Krauss{at}mssm.edu. Mailing address for Jong-Sun Kang: Samsung Biomedical Research Institute, SungKyunKwan University School of Medicine, Suwon 440-746, South Korea. Phone: 82-31-299-6135. Fax: 82-31-299-6435. E-mail: jskang{at}med.skku.ac.kr

{triangledown} Published ahead of print on 26 May 2009.

{dagger} Present address: Skirball Institute of Biomolecular Medicine, New York University, New York, NY 10016.

Molecular and Cellular Biology, August 2009, p. 4130-4143, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00199-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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