Regulation of inositol phospholipid binding and signaling through syndecan-4

被引:47
作者
Couchman, JR
Vogt, S
Lim, ST
Lim, Y
Oh, ES
Prestwich, GD
Theibert, A
Lee, W
Woods, A
机构
[1] Univ London Imperial Coll Sci Technol & Med, Fac Med, Div Biomed Sci, London SW7 2AZ, England
[2] Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Dept Neurobiol, Birmingham, AL 35294 USA
[4] Ewha Womans Univ, Dept Life Sci, Div Mol Life Sci, Seoul 120750, South Korea
[5] Ewha Womans Univ, Ctr Cell Signaling Res, Seoul 120750, South Korea
[6] Univ Utah, Dept Med Chem, Salt Lake City, UT 84108 USA
[7] Univ Utah, Ctr Cell Signaling, Salt Lake City, UT 84108 USA
[8] Yonsei Univ, Coll Sci, Dept Biochem, Seoul 120740, South Korea
[9] Yonsei Univ, Coll Sci, Prot Network Res Ctr, Seoul 120740, South Korea
关键词
D O I
10.1074/jbc.M209679200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Syndecan-4 is a transmembrane heparan sulfate proteoglyean that can regulate cell-matrix interactions and is enriched in focal adhesions. Its cytoplasmic domain contains a central region unlike that of any other vertebrate or invertebrate syndecan core protein with a cationic motif that binds inositol phospholipids. In turn, lipid binding stabilizes the syndecan in oligomeric form, with subsequent binding and activation of protein kinase C. The specificity of phospholipid binding and its potential regulation are investigated here. Highest affinity of the syndecan-4 cytoplasmic domain was seen with phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5P)(2)) and phosphatidylinositol 4-phosphate, and both promoted syndecan-4 oligomerization. Affinity was much reduced for 3-phosphorylated inositides while no binding of diacylglycerol was detected. Syndecan-2 cytoplasmic domain had negligible affinity for any lipid examined. Inositol hexakisphosphate, but not inositol tetrakisphosphate, also had high affinity for the syndecan-4 cytoplasmic domain and could compete effectively with PtdIns(4,5)P-2. Since inositol hexaphosphate binding to syndecan-4 does not promote oligomer formation, it is a potential down-regulator of syndecan-4 signaling. Similarly, phosphorylation of serine 183 in syndecan-4 cytoplasmic domain reduced PtdIns(4,5)P-2 binding affinity by over 100-fold, although interaction could still be detected by nuclear magnetic resonance spectroscopy. Only protein kinase Calpha was up-regulated in activity by the combination of syndecan-4 and PtdIns(4,5)P-2, with all other isoforms tested showing minimal response. This is consistent with the codistribution of syndecan-4 with the a isoform of protein kinase C in focal adhesions.
引用
收藏
页码:49296 / 49303
页数:8
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