Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor

Signaling through growth factor receptors controls Such diverse cell functi ons as proliferation, migration, and differentiation. A critical question h as been how the activation of these receptors is regulated. Most, if not al l, of the known ligands for these receptors are soluble factors. However, a s matrix components are highly tissue-specific and change during developmen t and pathology, it has been suggested that select growth factor receptors might be stimulated by binding to matrix components. Herein, we describe a new class of ligand for the epidermal growth factor (EGF) receptor (EGFR) f ound within the EGF-like repeats of tenascin-C, an antiadhesive matrix comp onent present during organogenesis, development, and wound repair. Select E GF-like repeats of tenascin-C elicited mitogenesis and EGFR autophosphoryla tion in an EGFR-dependent manner. Micromolar concentrations of EGF-like rep eats induced EGFR autophosphorylation and activated extracellular signal-re gulated, mitogen-activated protein kinase to levels comparable to those ind uced by subsaturating levels of known EGFR ligands. EGFR-dependent adhesion was noted when the ligands were tethered to inert beads, simulating the ph ysiologically relevant presentation of tenascin-C as hexabrachion, and sugg esting an increase in avidity similar to that seen for integrin ligands upo n surface binding. Specific binding to EGFR was further established by immu nofluorescence detection of EGF-like repeats bound to cells and cross-linki ng of EGFR with the repeats. Both of these interactions were abolished upon competition by EGF and enhanced by dimerization of the EGF-like repeat. Su ch low affinity behavior would be expected for a matrix-"tethered" ligand; i.e., a ligand which acts from the matrix, presented continuously to cell s urface EGF receptors, because it can neither diffuse away nor be internaliz ed and degraded. These data identify a new class of "insoluble" growth fact or ligands and a novel mode of activation for growth factor receptors.