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 functionalized 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
Mikaël M
MM
Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Hubbell
Jeffrey A
JA
D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D023822:Tissue Engineering; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D005353:Fibronectins; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D006493:Heparin