HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 49, 51289-51297, December 3, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/49/51289    most recent M408129200v3 M408129200v2 M408129200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jasuja, R. Articles by Greenspan, D. S. Search for Related Content PubMed PubMed Citation Articles by Jasuja, R. Articles by Greenspan, D. S. Social Bookmarking                      What's this?

Cell-surface Heparan Sulfate Proteoglycans Potentiate Chordin Antagonism of Bone Morphogenetic Protein Signaling and Are Necessary for Cellular Uptake of Chordin^*

Reema Jasuja, Benjamin L. Allen¶||, William N. Pappano||**, Alan C. Rapraeger¶, and Daniel S. Greenspan¶**¶¶

From the Programs in Molecular and Cellular Pharmacology and ^¶Cellular and Molecular Biology and the Departments of ^**Biomolecular Chemistry and Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706

Signaling by bone morphogenetic proteins (BMPs) plays a central role in early embryonic patterning, organogenesis, and homeostasis in a broad range of species. Chordin, an extracellular antagonist of BMP signaling, is thought to readily diffuse in tissues, thus forming gradients of BMP inhibition that result in reciprocal gradients of BMP signaling. The latter determine cell fates along the embryonic dorsoventral axis. The secreted protein Twisted Gastrulation (TSG) is thought to help shape BMP signaling gradients by acting as a cofactor that enhances Chordin inhibition of BMP signaling. Here, we demonstrate that mammalian Chordin binds heparin with an affinity similar to that of factors known to functionally interact with heparan sulfate proteoglycans (HSPGs) in tissues. We further demonstrate that Chordin binding in mouse embryonic tissues was dependent upon its interaction with cell-surface HSPGs and that Chordin bound to cell-surface HSPGs (e.g. syndecans), but not to basement membranes containing the HSPG perlecan. Surprisingly, mammalian TSG did not bind heparin unless prebound to Chordin and/or BMP-4, although Drosophila TSG has been reported to bind heparin on its own. Results are also presented that indicate that Chordin-HSPG interactions strongly potentiate the antagonism of BMP signaling by Chordin and are necessary for the retention and uptake of Chordin by cells. These data and others regarding Chordin diffusion have implications for the paradigm of how Chordin is thought to regulate BMP signaling in the extracellular space and how gradients of BMP signaling are formed.

Received for publication, July 19, 2004 , and in revised form, September 13, 2004.

^* This work was supported by National Institutes of Health Grants AR47746 and GM63471 (to D. S. G.) and Grant GM48850 (to A. C. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^|| Predoctoral Fellow of the American Heart Association.

To whom correspondence may be addressed: Dept. of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Ave., Madison, WI 53706. Tel.: 608-262-7577; Fax: 608-265-3301; E-mail: acraprae{at}wisc.edu. ¶¶ To whom correspondence may be addressed: Dept. of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Ave., Madison, WI 53706. Tel.: 608-262-4676; Fax: 608-262-6691; E-mail: dsgreens{at}wisc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. A. Khan, M. S. Nelson, C. Pan, P. M. Gaffney, and P. Gupta Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1387 - C1397. [Abstract] [Full Text] [PDF]

				D. J. Bornemann, S. Park, S. Phin, and R. Warrior A translational block to HSPG synthesis permits BMP signaling in the early Drosophila embryo Development, March 15, 2008; 135(6): 1039 - 1047. [Abstract] [Full Text] [PDF]

				J.-L. Zhang, Y. Huang, L.-Y. Qiu, J. Nickel, and W. Sebald von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms J. Biol. Chem., July 6, 2007; 282(27): 20002 - 20014. [Abstract] [Full Text] [PDF]

				R. Jasuja, G. Ge, N. G. Voss, J. Lyman-Gingerich, A. M. Branam, F. J. Pelegri, and D. S. Greenspan Bone Morphogenetic Protein 1 Prodomain Specifically Binds and Regulates Signaling by Bone Morphogenetic Proteins 2 and 4 J. Biol. Chem., March 23, 2007; 282(12): 9053 - 9062. [Abstract] [Full Text] [PDF]

				X. Jiao, P. C. Billings, M. P. O'Connell, F. S. Kaplan, E. M. Shore, and D. L. Glaser Heparan Sulfate Proteoglycans (HSPGs) Modulate BMP2 Osteogenic Bioactivity in C2C12 Cells J. Biol. Chem., January 12, 2007; 282(2): 1080 - 1086. [Abstract] [Full Text] [PDF]

				F. Rentzsch, J. Zhang, C. Kramer, W. Sebald, and M. Hammerschmidt Crossveinless 2 is an essential positive feedback regulator of Bmp signaling during zebrafish gastrulation Development, March 1, 2006; 133(5): 801 - 811. [Abstract] [Full Text] [PDF]

				M. B. O'Connor, D. Umulis, H. G. Othmer, and S. S. Blair Shaping BMP morphogen gradients in the Drosophila embryo and pupal wing Development, January 15, 2006; 133(2): 183 - 193. [Abstract] [Full Text] [PDF]

				C. Glister, S. L. Richards, and P. G. Knight Bone Morphogenetic Proteins (BMP) -4, -6, and -7 Potently Suppress Basal and Luteinizing Hormone-Induced Androgen Production by Bovine Theca Interna Cells in Primary Culture: Could Ovarian Hyperandrogenic Dysfunction Be Caused by a Defect in Thecal BMP Signaling? Endocrinology, April 1, 2005; 146(4): 1883 - 1892. [Abstract] [Full Text] [PDF]