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Published online September 1, 2008
doi:10.1083/jcb.200712110
The Journal of Cell Biology, Vol. 182, No. 5, 979-991
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Ren et al.
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Article

IGFBP-5 regulates muscle cell differentiation by binding to IGF-II and switching on the IGF-II auto-regulation loop



Hongxia Ren1, Ping Yin1, and Cunming Duan1,2

1 Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
2 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China

Correspondence to Cunming Duan: cduan{at}umich.edu

IGF-II stimulates both mitogenesis and myogenesis through its binding and activation of the IGF-I receptor (IGF-IR). How this growth factor pathway promotes these two opposite cellular responses is not well understood. We investigate whether local IGF binding protein-5 (IGFBP-5) promotes the myogenic action of IGF-II. IGFBP-5 is induced before the elevation of IGF-II expression during myogenesis. Knockdown of IGFBP-5 impairs myogenesis and suppresses IGF-II gene expression. IGF-II up-regulates its own gene expression via the PI3K-Akt signaling pathway. Adding IGF-II or constitutively activating Akt rescues the IGFBP-5 knockdown-caused defects. However, an IGF analogue that binds to the IGF-IR but not IGFBP has only a limited effect. When added with low concentrations of IGF-II, IGFBP-5 restores IGF-II expression and myogenic differentiation, whereas an IGF binding–deficient IGFBP-5 mutant has no effect. These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop.

H. Ren and P. Yin contributed equally to this paper.

Abbreviations used in this paper: DM, differentiation medium; IGF, insulin-like growth factor; IGFBP, IGF binding protein; IGF-IR, IGF-I receptor; MHC, myosin heavy chain; PI3K, phosphatidylinositol 3-kinase; TK, thymidine kinase.

© 2008 Ren 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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