Abstract
Fibronectin (FN), a major extracellular matrix component, enables integrin-mediated cell adhesion via binding of α5β1, αIIbβ3 and αv-class integrins to an RGD-motif. An additional linkage for α5 and αIIb is the synergy site located in close proximity to the RGD motif. We report that mice with a dysfunctional FN-synergy motif (Fn1syn/syn) suffer from surprisingly mild platelet adhesion and bleeding defects due to delayed thrombus formation after vessel injury. Additional loss of β3 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 α5β1 with the RGD, but essential to re-enforce the binding of α5β1/αIIbβ3 to FN. Our findings demonstrate a critical role for the FN synergy site when external forces exceed a certain threshold or when αvβ3 integrin levels decrease below a critical level.
Highlights
Fibronectin (FN) is a large extracellular matrix (ECM) glycoprotein that triggers biochemical and mechanical signaling via integrin binding
Blood vessel organization in whole mount ear samples analyzed by anti-PECAM-1 and anti-aSMA immunostainings revealed no abnormalities (Figure 1C), and the subendothelial matrix visualized with antibodies to laminin-1, collagen IV and FN, was normally organized in Fn1syn/syn mice (Figure 1—figure supplement 1E)
These data indicate that the FN synergy site is dispensable for development and postnatal homeostasis
Summary
Fibronectin (FN) is a large extracellular matrix (ECM) glycoprotein that triggers biochemical and mechanical signaling via integrin binding. FN is essential for mammalian development and tissue regeneration, and can influence disease such as cancer progression. FN is abundant in blood and in most tissues and is present in provisional matrices of healing wounds and in the stroma of tumors. FN consists of three different repeating Ig-like folded units, called type I-III modules. Whereas type I and II modules are stabilized by internal disulfide bonds, the 15 type III repeats of FN lack disulfide bonds, which confers elasticity to FN fibrils and the ability to modulate fibril rigidity (Erickson, 1994; Oberhauser et al, 2002). The major cell-binding site in FN is an arginine-glycine-aspartate (RGD) motif located in the 10th type III module (FNIII10) that is recognized by a5b1, aIIbb, and av-class integrins. In addition to the RGD motif, FN harbors the so-called FN synergy site in the FNIII9 module (Obara et al, 1988), which binds a5b1
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