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Published online 16 July 2001. doi:10.1083/jcb.200103103
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© The Rockefeller University Press, 0021-9525/2001/7/459 $5.00
The Journal of Cell Biology, Volume 154, Number 2, July 23, 2001 459-468

Article

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

C. Scott Swindle2, Kien T. Tran1, Terry D. Johnson4, Pallab Banerjee3, Anne M. Mayes3, Linda Griffith4 and Alan Wells1,2

1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
2 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
3 Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
4 Division of Bioengineering and Environmental Health and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139

Address correspondence to Alan Wells, Department of Pathology, 713 Scaife, University of Pittsburgh, Pittsburgh, PA 15261. Tel.: (412) 647-7813. Fax: (412) 647-8567. E-mail: wellsa{at}msx.upmc.edu

Signaling through growth factor receptors controls such diverse cell functions as proliferation, migration, and differentiation. A critical question has been how the activation of these receptors is regulated. Most, if not all, of the known ligands for these receptors are soluble factors. However, as matrix components are highly tissue-specific and change during development 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) found within the EGF-like repeats of tenascin-C, an antiadhesive matrix component present during organogenesis, development, and wound repair. Select EGF-like repeats of tenascin-C elicited mitogenesis and EGFR autophosphorylation in an EGFR-dependent manner. Micromolar concentrations of EGF-like repeats induced EGFR autophosphorylation and activated extracellular signal–regulated, mitogen-activated protein kinase to levels comparable to those induced by subsaturating levels of known EGFR ligands. EGFR-dependent adhesion was noted when the ligands were tethered to inert beads, simulating the physiologically relevant presentation of tenascin-C as hexabrachion, and suggesting an increase in avidity similar to that seen for integrin ligands upon surface binding. Specific binding to EGFR was further established by immunofluorescence detection of EGF-like repeats bound to cells and cross-linking of EGFR with the repeats. Both of these interactions were abolished upon competition by EGF and enhanced by dimerization of the EGF-like repeat. Such low affinity behavior would be expected for a matrix-"tethered" ligand; i.e., a ligand which acts from the matrix, presented continuously to cell surface EGF receptors, because it can neither diffuse away nor be internalized and degraded. These data identify a new class of "insoluble" growth factor ligands and a novel mode of activation for growth factor receptors.

Key Words: receptor signaling; cell–substratum interactions; adhesion; extracellular matrix; tissue engineering


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