The syndecans are known to form homologous oligomers that may be important for their functions. We have therefore determined the role of oligomerization of syndecan-2 and syndecan-4. A series of glutathione S-transferase-syndecan-2 and syndecan-4 chimeric proteins showed that all syndecan constructs containing the transmembrane domain formed SDS-resistant dimers, but not those lacking it. SDS-resistant dimer formation was hardly seen in the syndecan chimeras where each transmembrane domain was substituted with that of platelet-derived growth factor receptor (PDGFR). Increased MAPK activity was detected in HEK293T cells transfected with syndecan/PDGFR chimeras in a syndecan transmembrane domain-dependent fashion. The chimera-induced MAPK activation was independent of both ligand and extracellular domain, implying that the transmembrane domain is sufficient to induce dimerization/oligomerization in vivo. Furthermore, the syndecan chimeras were defective in syndecan-4-mediated focal adhesion formation and protein kinase C␣ activation or in syndecan-2-mediated cell migration. Taken together, these data suggest that the transmembrane domains are sufficient for inducing dimerization and that transmembrane domain-induced oligomerization is crucial for syndecan-2 and syndecan-4 functions.The syndecans are a major family of transmembrane cell surface heparan sulfate proteoglycans that are developmentally regulated with tissue-specific distributions (1, 2). Syndecan-2 is abundantly expressed in mesenchymal cells, whereas syndecan-1 and syndecan-3 are characteristic of epithelial and neuronal cells (2-5). All syndecans are type I transmembrane receptor proteins, with an N-terminal signal peptide, an ectodomain containing several consensus sequences for glycosaminoglycan attachment, a putative protease cleavage site proximal to the membrane, a single hydrophobic transmembrane domain, and a short C-terminal cytoplasmic domain (2-4). Their extracellular domain sequences are very distinct, but transmembrane domain and cytoplasmic domain sequences are highly conserved (2-4, 6), implying a possible biological role for the cytoplasmic domain. Indeed, during cell-cell and/or cell-matrix interaction, syndecans have important roles as cell surface receptors (6 -8).It is common that signaling through cell surface receptor proteins containing a single transmembrane domain is transduced by noncovalent dimerization of the proteins in response to ligand binding (9, 10). In the case of the platelet-derived growth factor (PDGF) 3 receptor (PDGFR), ligand stimulation of the PDGFR leads to receptor dimerization, activation of the kinase activity of the receptor, and phosphorylation of the receptor at numerous intracellular tyrosine residues. Subsequently, various molecules containing Src homology domains are recruited to the PDGFR where they act as signaling enzymes and adapter molecules (11,12).The possible participation of syndecans in signaling was first suggested by the findings that syndecan-4 is a component of focal adhesions (13), whe...
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