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J. Biol. Chem., Vol. 281, Issue 34, 24365-24374, August 25, 2006

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Syndecan-1 Expression in Epithelial Cells Is Induced by Transforming Growth Factor through a PKA-dependent Pathway^*

Kazutaka Hayashida, Douglas R. Johnston, Olga Goldberger, and Pyong Woo Park^¶||1

From the Departments of Medicine, ^¶Molecular and Cellular Biology, and ^||Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030 and the Division of Newborn Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Syndecans comprise a major family of cell surface heparan sulfate proteoglycans (HSPGs). Syndecans bind and modulate a wide variety of biological molecules through their heparan sulfate (HS) moiety. Although all syndecans contain the ligand binding HS chains, they likely perform specific functions in vivo because their temporal and spatial expression patterns are different. However, how syndecan expression is regulated has yet to be clearly defined. In this study, we examined how syndecan-1 expression is regulated in epithelial cells. Our results showed that among several bioactive agents tested, only forskolin and three isoforms of TGF (TGF1-TGF3) significantly induced syndecan-1, but not syndecan-4, expression on various epithelial cells. Steady-state syndecan-1 mRNA was not increased by TGF treatment and cycloheximide did not inhibit syndecan-1 induction by TGF, indicating that TGF induces syndecan-1 in a post-translational manner. However, TGF induction of syndecan-1 was inhibited by transient expression of a dominant-negative construct of protein kinase A (PKA) and by specific inhibitors of PKA. Further (i) syndecan-1 cytoplasmic domains were Ser-phosphorylated when cells were treated with TGF and this was inhibited by a PKA inhibitor, (ii) PKA was co-immunoprecipitated from cell lysates by anti-syndecan-1 antibodies, (iii) PKA phosphorylated recombinant syndecan-1 cytoplasmic domains in vitro, and (iv) expression of a syndecan-1 construct with its invariant Ser²⁸⁶ replaced with a Gly was not induced by TGF. Together, these findings define a regulatory mechanism where TGF signals through PKA to phosphorylate the syndecan-1 cytoplasmic domain and increases syndecan-1 expression on epithelial cells.

Received for publication, August 24, 2005 , and in revised form, June 16, 2006.

^* This work was supported in part by Grants HL69050 and HL73725 from the National Institutes of Health and a Career Investigator Award from the American Lung Association. 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.

¹ To whom correspondence should be addressed: Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Rm. N1319, Houston, TX 77030. Tel.: 713-798-4504; Fax: 713-798-8948; E-mail: pwpark{at}bcm.tmc.edu.

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