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Published 27 September 2004. doi:10.1083/jcb.200402138
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 7, 1081-1091
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Article

CD44 modulates Smad1 activation in the BMP-7 signaling pathway



Richard S. Peterson1, Roma A. Andhare1, Kathleen T. Rousche1, Warren Knudson1,2, Weihua Wang1, Jami B. Grossfield3, Raymond O. Thomas3, Robert E. Hollingsworth3, and Cheryl B. Knudson1,2

1 Department of Biochemistry, Rush Medical College, Rush University Medical Center, Chicago, IL 60612
2 Department of Pathology, Rush Medical College, Rush University Medical Center, Chicago, IL 60612
3 Pathway Discovery, Genomic and Proteomic Sciences, GlaxoSmithKline, Inc., Research Triangle Park, NC 27709

Address correspondence to Cheryl B. Knudson, Dept. of Biochemistry, Rush Medical College, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612. Tel.: (312) 942-8249. Fax: (312) 942-3053. email: cheryl_knudson{at}rush.edu

Bone morphogenetic protein 7 (BMP-7) regulates cellular metabolism in embryonic and adult tissues. Signal transduction occurs through the activation of intracellular Smad proteins. In this paper, using a yeast two-hybrid screen, Smad1 was found to interact with the cytoplasmic domain of CD44, a receptor for the extracellular matrix macromolecule hyaluronan. Coimmunoprecipitation experiments confirmed the interaction of Smad1 with full-length CD44—interactions that did not occur when CD44 receptors truncated within the cytoplasmic domain were tested. Chondrocytes overexpressing a truncated CD44 on a background of endogenous full-length CD44 no longer exhibited Smad1 nuclear translocation upon BMP-7 stimulation. Further, pretreatment of chondrocytes with Streptomyces hyaluronidase to disrupt extracellular hyaluronan–cell interactions inhibited BMP-7–mediated Smad1 phosphorylation, nuclear translocation of Smad1 or Smad4, and SBE4–luciferase reporter activation. These results support a functional link between the BMP signaling cascade and CD44. Thus, changes in hyaluronan–cell interactions may serve as a means to modulate cellular responsiveness to BMP.

Key Words: CD44; bone morphogenetic protein; hyaluronan; chondrocyte; Smad1

R.S. Peterson and R.A. Andhare contributed equally to this paper.

Abbreviations used in this paper: BMP, bone morphogenetic protein; SBE, Smad-binding element.


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