The fibronectin synergy site re-enforces cell adhesion and mediates a crosstalk between integrin classes

Fibronectin (FN), a major extracellular matrix component, enables integrin-mediated cell adhesion via binding of alpha 5 beta 1, alpha IIb beta 3 and alpha v-class integrins to an RGD-motif. An additional linkage for alpha 5 and alpha IIb is the synergy site located in close proximity to the RGD motif. We report that mice with a dysfunctional FN-synergy motif (Fn1(syn/syn)) suffer from surprisingly mild platelet adhesion and bleeding defects due to delayed thrombus formation after vessel injury. Additional loss of beta 3 integrins dramatically aggravates the bleedings and severely compromises smooth muscle cell coverage of the vasculature leading to embryonic lethality. Cell-based studies revealed that the synergy site is dispensable for the initial contact of alpha 5 beta 1 with the RGD, but essential to re-enforce the binding of alpha 5 beta 1/alpha IIb beta 3 to FN. Our findings demonstrate a critical role for the FN synergy site when external forces exceed a certain threshold or when alpha v beta 3 integrin levels decrease below a critical level