Syndecan-1 expression in epithelial cells is induced by transforming growth factor beta through a PKA-dependent pathway.
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 TGFbeta (TGFbeta1-TGFbeta3) significantly induced syndecan-1, but not syndecan-4, expression on various epithelial cells. Steady-state syndecan-1 mRNA was not increased by TGFbeta treatment and cycloheximide did not inhibit syndecan-1 induction by TGFbeta, indicating that TGFbeta induces syndecan-1 in a post-translational manner. However, TGFbeta 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 TGFbeta 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 Ser(286) replaced with a Gly was not induced by TGFbeta. Together, these findings define a regulatory mechanism where TGFbeta signals through PKA to phosphorylate the syndecan-1 cytoplasmic domain and increases syndecan-1 expression on epithelial cells.
Hayashida
Kazutaka
K
Departments of Medicine, Molecular and Cellular Biology, and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA.
Johnston
Douglas R
DR
Goldberger
Olga
O
Park
Pyong Woo
PW
D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1; D053667:Syndecans; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011509:Proteoglycans; D011994:Recombinant Proteins; C508241:SDC1 protein, human; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; D016212:Transforming Growth Factor beta; D005576:Colforsin; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases