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.
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23 July 2001
Article|
July 16 2001
Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor
C. Scott Swindle,
C. Scott Swindle
2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
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Kien T. Tran,
Kien T. Tran
1Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
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Terry D. Johnson,
Terry D. Johnson
4Division of Bioengineering and Environmental Health and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Pallab Banerjee,
Pallab Banerjee
3Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Anne M. Mayes,
Anne M. Mayes
3Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Linda Griffith,
Linda Griffith
4Division of Bioengineering and Environmental Health and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Alan Wells
Alan Wells
1Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
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C. Scott Swindle
2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
Kien T. Tran
1Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
Terry D. Johnson
4Division of Bioengineering and Environmental Health and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
Pallab Banerjee
3Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
Anne M. Mayes
3Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
Linda Griffith
4Division of Bioengineering and Environmental Health and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
Alan Wells
1Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
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: [email protected]
C. Scott Swindle and Kien T. Tran contributed equally to this work.
*
Abbreviations used in this paper: EGFR, EGF receptor; ERK, extracellular signal–regulated kinase; M, mutant; MAP, mitogen-activated protein; mEGF, murine EGF; PEO, polyethylene oxide; WT, wild-type.
Received:
March 22 2001
Revision Received:
May 24 2001
Accepted:
May 29 2001
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2001
J Cell Biol (2001) 154 (2): 459–468.
Article history
Received:
March 22 2001
Revision Received:
May 24 2001
Accepted:
May 29 2001
Citation
C. Scott Swindle, Kien T. Tran, Terry D. Johnson, Pallab Banerjee, Anne M. Mayes, Linda Griffith, Alan Wells; Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor . J Cell Biol 23 July 2001; 154 (2): 459–468. doi: https://doi.org/10.1083/jcb.200103103
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