Figure 9
Model—postulated mechanism for polarized invasion mechanism induced by HPSE. (a) Clustering of VLA-4 to membrane domains leads to increased avidity and strengthening of adhesion to FN or VCAM-1. Paxillin bound to the alpha4 cytoplasmic domain causes inherent inhibition of Rac GTPase at this site. Trimming of the HS chains on Sdc1 facilitates its recognition and shedding by MMP-9. (b) Sdc1 freed of its membrane anchorage engages VEGFR2 and VLA-4 via its juxtamembrane receptor capture site (amino acids 210–236), coupling VEGFR2 to the VLA-4 clusters. VEGFR2 activated by the Sdc1-mediated clustering event initiates downstream signaling that displaces paxillin, allows localized activation of Rac GTPase and triggers polarized migration. (c) Synstatin peptides that bind either VEGFR2 alone (SSTN210-233) or VLA-4 alone (SSTN214-236) compete for Sdc1-mediated receptor capture and block the activation mechanism.
