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Vol. 16, Issue 6, 2984-2998, June 2005

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The Membrane-anchoring Domain of Epidermal Growth Factor Receptor Ligands Dictates Their Ability to Operate in Juxtacrine Mode

Jianying Dong ^* , Lee K. Opresko , William Chrisler , Galya Orr , Ryan D. Quesenberry , Douglas A. Lauffenburger , and H. Steven Wiley 

^* Department of Pathology, Division of Cell Biology and Immunology, University of Utah, Salt Lake City, UT 84133; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352; and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139

Submitted November 16, 2004; Revised March 30, 2005; Accepted March 31, 2005
Monitoring Editor: Carl-Henrik Heldin

All ligands of the epidermal growth factor (EGF) receptor (EGFR) are synthesized as membrane-anchored precursors. Previous work has suggested that some ligands, such as EGF, must be proteolytically released to be active, whereas others, such as heparin-binding EGF-like growth factor (HB-EGF) can function while still anchored to the membrane (i.e., juxtacrine signaling). To explore the structural basis for these differences in ligand activity, we engineered a series of membrane-anchored ligands in which the core, receptor-binding domain of EGF was combined with different domains of both EGF and HB-EGF. We found that ligands having the N-terminal extension of EGF could not bind to the EGFR, even when released from the membrane. Ligands lacking an N-terminal extension, but possessing the membrane-anchoring domain of EGF, still required proteolytic release for activity, whereas ligands with the membrane-anchoring domain of HB-EGF could elicit full biological activity while still membrane anchored. Ligands containing the HB-EGF membrane anchor, but lacking an N-terminal extension, activated EGFR during their transit through the Golgi apparatus. However, cell-mixing experiments and fluorescence resonance energy transfer studies showed that juxtacrine signaling typically occurred in trans at the cell surface, at points of cell-cell contact. Our data suggest that the membrane-anchoring domain of ligands selectively controls their ability to participate in juxtacrine signaling and thus, only a subclass of EGFR ligands can act in a juxtacrine mode.

Present address: Abgenix, 6701 Kaiser Dr., Fremont, CA 94555.

Address correspondence to: H. Steven Wiley (steven.wiley{at}pnl.gov).

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