Fibronectin at select sites binds multiple growth factors and enhances their activity: expansion of the collaborative ECM-GF paradigm

Abstract

Intensive research has demonstrated that extracellular matrix (ECM) molecules and growth factors (GF) collaborate at many different levels. The ability of ECM to modulate GF signals has important implications in tissue formation and homeostasis as well as novel therapies for acute and chronic wounds. Recently, a number of GF-binding sites was identified in fibronectin (FN) and was shown to provide another layer of regulation on GF signaling. Here, we review these new findings on FN interaction with GF in the context of general ways ECM molecules regulate GF signaling.

Figure 1. ECM regulation of GF signaling dependent on ECM-GF binding

a) ECM serves as a reservoir of GF to spatially regulate its bioavailability. b) GF tethered to ECM through growth factor-binding domain is presented as solid phase ligand that generates protracted signaling. c) The juxtaposition of growth factor-binding domain and integrin binding site in ECM facilitates the formation of adhesion complexes, the structural basis for the synergistic signaling of ECM and GF. d) Proteolytic processing not only releases ECM sequestered GF; it also generates bioactive peptides that can directly bind GF and enhance GF signaling.

Figure 2. ECM regulation of GF signaling independent of ECM-GF binding

a) ECM and GF generate signals that activate the same pathway synergistically. b) The type or stiffness of ECM pre-conditions the cell and regulates the outcome of GF signaling. c) ECM can also activate GFR in the absence of GF either through integrin or direct binding to GFR. d) ECM generates signals through integrin to regulate the expression level (recycling) of GFR or GF.