Vascular endothelial‐cadherin stimulates syndecan‐1‐coupled insulin‐like growth factor‐1 receptor and cross‐talk between αVβ3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis

Abstract

VEGF-stimulated angiogenesis depends on a cross-talk mechanism involving VEGF receptor 2 (VEGFR2), vascular endothelial (VE)-cadherin and the αVβ3 integrin. Since we have shown that αVβ3 integrin activation is dependent on its incorporation, along with the insulin-like growth factor-1 receptor (IGF1R) kinase, into a ternary receptor complex organized by the matrix receptor syndecan-1 (Sdc1), we questioned the role of this core complex in VEGF-stimulated angiogenesis. We find that the Sdc1-coupled ternary receptor complex is required for VEGF signaling and for stimulation of vascular endothelial cell migration by VE-cadherin engagement. VE-cadherin binding to Fc/VE-cadherin chimeras activates Sdc1-coupled IGF1R and αVβ3 integrin; this depends on VEGFR2 and c-Src activated by the cadherin. Blocking homotypic VE-cadherin engagement disrupts VEGF-stimulated cell migration, which is restored by clustering the cadherin in the absence of cell-cell adhesion. This cadherin-dependent stimulation requires VEGFR2 and IGF1R and is blocked by synstatin (SSTN92-119), a peptide that competitively disrupts the Sdc1-coupled ternary complex and prevents αVβ3 integrin activation that is required for VEGFR2 activation. VEGFR2-stimulated angiogenesis in the mouse aortic ring explant assay is disrupted by SSTN, but only early in the process, suggesting that IGF1R coupling to Sdc1 and αVβ3 integrin comprises a core activation mechanism activated by VE-cadherin that is necessary for VEGFR2 and integrin activation during the initial stages of endothelial cell dissemination during angiogenesis.

Syndecan-1 and Syndecan-4 Capture Epidermal Growth Factor Receptor Family Members and the α3β1 Integrin Via Binding Sites in Their Ectodomains

“…Our findings build on a paradigm first established several years ago when Sdc1 was shown to organize a different receptor complex, namely, the insulin-like growth factor-1 receptor (IGF-1R) associated with the ␣v␤3 or ␣v␤5 integrin (31)(32)(33)(34). In this example, the association is mediated by a 28 amino acid site in the Sdc1 extracellular domain, which binds to both the integrin and IGF-1R and captures them into a functional complex.…”

Shed syndecan-2 inhibits angiogenesis

“…Journal of Cell Science (2014Science ( ) 127, 4788-4799 doi:10.1242 characteristics through an autocrine interaction with IGFR-1 (Beauvais and Rapraeger, 2010;Rapraeger et al, 2013). We propose that shed syndecan-2 acts in a paracrine fashion given that the adhesion regulatory domain of syndecan-2 is situated very close to the transmembrane domain of the full-length molecule.…”

Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation

“…Thus, in the absence of MMP7, neutrophils would retain ligation to the negative signal. This model implies that MMP7 shedding of syndecan-1 could affect the activity of the putative repressor, and, indeed, shedding of syndecans does affect the activation state of other receptors, such as integrins (11,(41)(42)(43)(44)(45). Although this possible mechanism appears attractive, the specific means by which epithelial cells can constrain neutrophil activation remain to be determined.…”