Regulation of inositol phospholipid binding and signaling through syndecan-4.

John R Couchman; Susan Vogt; Ssang-Taek Lim; Yangmi Lim; Eok-Soo Oh; Glenn D Prestwich; Anne Theibert; Weontae Lee; Anne Woods

doi:10.1074/jbc.M209679200

Regulation of inositol phospholipid binding and signaling through syndecan-4.

John R Couchman, Susan Vogt, Ssang-Taek Lim, Yangmi Lim, Eok-Soo Oh, Glenn D Prestwich, Anne Theibert, Weontae Lee, Anne Woods

Nutritional Immunology

46 Citations (Scopus)

Abstract

Syndecan-4 is a transmembrane heparan sulfate proteoglycan 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 alpha isoform of protein kinase C in focal adhesions.

Original language	English
Journal	Journal of Biological Chemistry
Volume	277
Issue number	51
Pages (from-to)	49296-303
Number of pages	7
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M209679200
Publication status	Published - 2002

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@article{d20456f0596d11dd8d9f000ea68e967b,

title = "Regulation of inositol phospholipid binding and signaling through syndecan-4.",

abstract = "Syndecan-4 is a transmembrane heparan sulfate proteoglycan 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 alpha isoform of protein kinase C in focal adhesions.",

author = "Couchman, {John R} and Susan Vogt and Ssang-Taek Lim and Yangmi Lim and Eok-Soo Oh and Prestwich, {Glenn D} and Anne Theibert and Weontae Lee and Anne Woods",

note = "Keywords: Amino Acid Sequence; Animals; Binding, Competitive; Cell Adhesion; Cells, Cultured; Cytoplasm; Dose-Response Relationship, Drug; Enzyme Activation; Gene Expression Regulation; Humans; Inositol; Isoenzymes; Lipid Metabolism; Magnetic Resonance Spectroscopy; Membrane Glycoproteins; Models, Chemical; Molecular Sequence Data; Phosphatidylinositol Phosphates; Phospholipids; Phosphorylation; Protein Binding; Protein Isoforms; Protein Kinase C; Protein Kinase C-alpha; Protein Structure, Tertiary; Proteoglycans; Rats; Serine; Signal Transduction; Syndecan-4; Up-Regulation",

year = "2002",

doi = "10.1074/jbc.M209679200",

language = "English",

volume = "277",

pages = "49296--303",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

number = "51",

}

TY - JOUR

T1 - Regulation of inositol phospholipid binding and signaling through syndecan-4.

AU - Couchman, John R

AU - Vogt, Susan

AU - Lim, Ssang-Taek

AU - Lim, Yangmi

AU - Oh, Eok-Soo

AU - Prestwich, Glenn D

AU - Theibert, Anne

AU - Lee, Weontae

AU - Woods, Anne

N1 - Keywords: Amino Acid Sequence; Animals; Binding, Competitive; Cell Adhesion; Cells, Cultured; Cytoplasm; Dose-Response Relationship, Drug; Enzyme Activation; Gene Expression Regulation; Humans; Inositol; Isoenzymes; Lipid Metabolism; Magnetic Resonance Spectroscopy; Membrane Glycoproteins; Models, Chemical; Molecular Sequence Data; Phosphatidylinositol Phosphates; Phospholipids; Phosphorylation; Protein Binding; Protein Isoforms; Protein Kinase C; Protein Kinase C-alpha; Protein Structure, Tertiary; Proteoglycans; Rats; Serine; Signal Transduction; Syndecan-4; Up-Regulation

PY - 2002

Y1 - 2002

N2 - Syndecan-4 is a transmembrane heparan sulfate proteoglycan 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 alpha isoform of protein kinase C in focal adhesions.

AB - Syndecan-4 is a transmembrane heparan sulfate proteoglycan 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 alpha isoform of protein kinase C in focal adhesions.

U2 - 10.1074/jbc.M209679200

DO - 10.1074/jbc.M209679200

M3 - Journal article

C2 - 12377772

SN - 0021-9258

VL - 277

SP - 49296

EP - 49303

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 51

ER -

Regulation of inositol phospholipid binding and signaling through syndecan-4.

Abstract

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