Syndecan-1 adhesion-mediated signaling in human mammary carcinomas. In response to syndecan-1 ligation, αvβ3 integrins and syndecan-1 form a signaling complex that regulates cytoskeletal reorganization. Cells initially fail to spread in response to syndecan-1 ligation because signaling downstream of this complex is negatively regulated by activated α2β1 integrins. Treatment of cells with a neutralizing β1 integrin antibody relieves this inhibitory signal allowing cells to initiate a spreading response. Intriguingly, signaling occurs in the absence of an integrin ligand suggesting that syndecan-1 participates in the allosteric activation of αvβ3 integrins. While activated αvβ3 integrins are required for signaling (i.e. spreading is blocked by αvβ3 integrin blocking antibody), molecular interactions of the syndecan-1 core protein are also required as signaling is blocked by soluble m urine s yndecan-1 e ctod omain (mS1ED). In our model, the syndecan physically associates with the αvβ3 integrin via an ectodomain interaction, although a functional coupling via an indirect mechanism has not been ruled out. Further, while our data suggest that the syndecan's transmembrane and cytoplasmic domains are not absolutely required for signaling, the possibility that these domains may have important regulatory roles cannot be excluded.