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A Cdo–Bnip-2–Cdc42 signaling pathway regulates p38/β MAPK activity and myogenic differentiation

¹ Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029
² Samsung Biomedical Research Institute, SungKyunKwan University School of Medicine, Suwon 440-746, South Korea
³ Department of Biological Sciences, National University of Singapore, Singapore 117543, Republic of Singapore

Correspondence to Robert S. Krauss: Robert.Krauss{at}mssm.edu; or Jong-Sun Kang: jskang{at}med.skku.ac.kr

The p38/β mitogen-activated protein kinase (MAPK) pathway promotes skeletal myogenesis, but the mechanisms by which it is activated during this process are unclear. During myoblast differentiation, the promyogenic cell surface receptor Cdo binds to the p38/β pathway scaffold protein JLP and, via JLP, p38/β itself. We report that Cdo also interacts with Bnip-2, a protein that binds the small guanosine triphosphatase (GTPase) Cdc42 and a negative regulator of Cdc42, Cdc42 GTPase-activating protein (GAP). Moreover, Bnip-2 and JLP are brought together through mutual interaction with Cdo. Gain- and loss-of-function experiments with myoblasts indicate that the Cdo–Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38/β activity and cell differentiation. These results reveal a previously unknown linkage between a cell surface receptor and downstream modulation of Cdc42 activity. Furthermore, interaction with multiple scaffold-type proteins is a distinctive mode of cell surface receptor signaling and provides one mechanism for specificity of p38/β activation during cell differentiation.

G. Takaesu's present address is Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

Abbreviations used in this paper: β-gal, β-galactosidase; DM, differentiation medium; GAP, GTPase-activating protein; GM, growth medium; MHC, myosin heavy chain.

© 2008 Kang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Oh, J.-E., Bae, G.-U., Yang, Y.-J., Yi, M.-J., Lee, H.-J., Kim, B.-G., Krauss, R. S., Kang, J.-S. (2009). Cdo promotes neuronal differentiation via activation of the p38 mitogen-activated protein kinase pathway. FASEB J. 23: 2088-2099 [Abstract] [Full Text]  

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