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After phosphorylation of serine residue of the cytoplasmic domain of syndecan-2 was demonstrated in mouse lung carcinoma cells in situ,3) phosphorylation of other syndecans were sought. Phosphorylation of serine residue of syndecan-3 using a synthetic peptide, tyrosine residue of syndecan-1 using transfectants, and serine residue of syndecan-4 in fibroblast in situ were reported.4,5) However, the biological significance of phosphorylation/dephosphorylation in these amino acid residues has not been elucidated.
Efforts to detect cytoplasmic proteins which interact with syndecans did not obtain any results for a long time. However, very recently it was demonstrated with a yeast two-hybrid screening method that the cytoplasmic portion of syndecans binds syntenin containing a tandem repeat of the PDZ domain 6) and that the PDZ domain of CASK binds syndecan-2.7,8) Syndecans bound to the PDZ domain with its C-terminus EFYA sequence, CASK was also bound to actin-binding protein 4.1 via it's another domain, and CASK colocalized to syndecan-1, suggesting that the binding ability to the PDZ domain is common to all family members and that the binding signal transducs to the cytoskeleton organization. It was also demonstrated that cortactin, an F-actin-binding protein which is a major substrate to Src kinase, bound to the immobilized cytoplasmic portion of syndecan-3.9) This binding was competed with the peptide of the membrane proximal common sequence of the syndecan cytoplasmic portion. At present there are fragmentary reports concerning syndecan signal transduction, but it is expected that these pieces of evidence will come together gradually and a whole picture of the puzzle will appear in the near feature. Nevertheless, it should be noted that nothing has been coprecipitated with syndecans by anti-syndecan antibodies in spite of every effort. This is attributed to the extraction conditions used. However, if this is a case of Sherlock Holmes' "the curious incident of the dog in the night-time," it will not be so easy to solve the problem.
Dally, Drosophila homolog of glypican, another cell membrane-type heparan sulfate proteoglycan with a GPI anchor, has been detected in association with a mutation of abnormal cell division, and analyses of the signal cascade involved with glypican as a receptor of TGF-beta homolog, Dpp, are now actively being studied. Drosophila homolog of the syndecan gene has also been cloned. However, a mutant fly linking with syndecan has not been found out, thus an analysis has not progressed in this system either. If the mutant is found out, the information will contribute to understand signal transductions mediated by syndecans. |
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References |
(1) |
Wood, A, Couchman, JR: Syndecans: synergistic activators of cell adhesion. Trends Cell Biol. 8, 189-92, 1998 |
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(2) |
Carey, DJ : Syndecans: multifunctional cell-surface co-receptors. Biochem. J. 327, 1-16, 1997 |
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(3) |
N, Itano, K, Oguri, Y, Nagayasu, Y, Kusano, H, Nakanishi, G, David, M, Okayama : Phosphorylation of a membrane-intercalated proteoglycan, syndecan-2, expressed in a stroma-inducing clone from a mouse Lewis lung carcinoma. Biochem. J. 315: 925-930, 1996 |
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(4) |
Horowitz, A, Simons, M : Regulation of syndecan-4 phosphorylation in vivo. J. Biol. Chem., 273: 10914-10918, 1998 |
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(5) |
Horowitz, A, Simons, M : Phosphorylation of the cytoplasmic tail of syndecan-4 regulates activation of protein kinase Ca. J. Biol. Chem. 273, 25548-25551, 1998 |
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(6) |
JJ, Grootjans, P, Zimmermann, G, Reekmans, A, Smets, G, Degeest, J, Durr, G, David : Syntenin, 1 PDZ protein that binds syndecan cytoplasmic domains. Proc. Natl. Acad. Sci. USA, 94, 13683-13688, 1997 |
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(7) |
AR, Cohen, DF, Wood, SM, Marfatia, Z, Walther, AH, Chishti, JM, Anderson : Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. J. Cell Biol. 142, 129-138, 1998 |
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(8) |
Y-P, Hsueh, F-C, Yang, V, Kharazia, S, Naisbitt, AR, Cohen, RJ, Weinberg, M, Sheng : Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. J. Cell Biol. 142, 139-151, 1998 |
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(9) |
T, Kinnunen, M, Kaksonen, J, Saarinen, N, Kalkkinen, HB, Peng, H, Rauvala : Cortactin-Src kinase signaling pathway is involved in N-syndecan-dependent neurite outgrowth. J. Biol. Chem. 273, 10702-10708, 1998 |
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