The 12th–14th type III repeats of fibronectin function as a highly promiscuous growth factor‐binding domain

It has recently been shown that some growth factors (GFs) have strong interactions with nonproteoglycan extracellular matrix proteins. Relevant here, the 12th‐14th type three repeats of fibronectin (FN III12–14) have been shown to bind insulin‐like growth factor binding‐protein‐3, fibroblast growth factor (FGF)‐2, and vascular endothelial growth factor (VEGF)‐A with high affinity. Since FN III12–14 is known to bind GFs from different families, we hypothesized that this domain could be highly promiscuous in its GF‐binding capacity. We used biochemical approaches and surface plasmon resonance to investigate such interactions with recombinant FN III12–14. We found that FN III12–14 binds most of the GFs from the platelet‐derived growth factor (PDGF)/VEGF and FGF families and some GFs from the transforming growth factor‐β and neurotrophin families, with K D values in the nanomolar range, without inhibiting GF activity. Overall, 25 new binding interactions were identified. In a clinically relevant fibrin matrix, a fibrin‐binding variant of FN III12–14 was highly effective as a GF delivery system. For instance, in matrices functional‐ized with FN III12–14, PDGF‐BB‐induced sprouting of human smooth muscle cell spheroids was greatly enhanced. We show that FN III12–14 is a highly promiscuous ligand for GFs and also holds great potential in clinical healing applications.—Martino, M. M., Hubbell, J. A. The 12th‐14th type III repeats of fibronectin function as a highly promiscuous growth factor binding domain. FASEB J. 24, 4711–4721 (2010). www.fasebj.org