Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation

Syndecan-1 (Sdc1) engages and activates the alpha v beta 3 (and/or alpha v beta 5) integrin when clustered in human carcinoma and endothelial cells. Although the engagement is extracellular, the activation mechanism is cytoplasmic. This talin-dependent, inside-out signaling pathway is activated downstream of the insulin-like growth factor-1 receptor (IGF1R), whose kinase activity is triggered by Sdc1 clustering. In vitro binding assays using purified receptors suggest that association of the Sdc1 ectodomain with the integrin provides a 'docking face' for IGF1R. IGF1R docking and activation of the associated integrin is blocked by synstatin (SSTN(92-119)), a peptide derived from the integrin engagement site in Sdc1. IGF1R colocalizes with alpha v beta 3 integrin and Sdc1 in focal contacts, but fails to associate with or activate the integrin in cells either lacking Sdc1 or expressing Sdc1(Delta 67-121), a mutant that is unable to form the Sdc1-integrin-IGF1R ternary complex. Integrin activation is also blocked by IGF1R inhibitors or by silencing IGF1R or talin expression with small-interfering RNAs (siRNAs). In both cases, expression of the constitutively active talin F23 head domain rescues integrin activation. We recently reported that SSTN(92-119) blocks angiogenesis and impairs tumor growth in mice, therefore this Sdc1-mediated integrin regulatory mechanism might be a crucial regulator of disease processes known to rely on these integrins, including tumor cell metastasis and tumor-induced angiogenesis.