The heparin-binding domain of HB-EGF mediates localization to sites of cell-cell contact and prevents HB-EGF proteolytic release
Name
Prince J Cell Sci 2010.pdf
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2.36 MB
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Author(s)
Prince, Robin N.
Schreiter, Eric R.
Zou, Peng
Wiley, H. Steven
Ting, Alice Y.
Lee, Richard T.
Lauffenburger, Douglas A.
Date Issued
June 2010
Journal
Journal of Cell Science
Publisher
Company of Biologists, The
Citation
Prince, R. N. et al. “The Heparin-binding Domain of HB-EGF Mediates Localization to Sites of Cell-cell Contact and Prevents HB-EGF Proteolytic Release.” Journal of Cell Science 123.13 (2010): 2308–2318. The Company of Biologists Ltd 2010
Version
Final published version
Abstract
Heparin-binding EGF-like growth factor (HB-EGF) is a ligand for EGF receptor (EGFR) and possesses the ability to signal in juxtacrine, autocrine and/or paracrine mode, with these alternatives being governed by the degree of proteolytic release of the ligand. Although the spatial range of diffusion of released HB-EGF is restricted by binding heparan-sulfate proteoglycans (HSPGs) in the extracellular matrix and/or cellular glycocalyx, ascertaining mechanisms governing non-released HB-EGF localization is also important for understanding its effects. We have employed a new method for independently tracking the localization of the extracellular EGF-like domain of HB-EGF and the cytoplasmic C-terminus. A striking observation was the absence of the HB-EGF transmembrane pro-form from the leading edge of COS-7 cells in a wound-closure assay; instead, this protein localized in regions of cell-cell contact. A battery of detailed experiments found that this localization derives from a trans interaction between extracellular HSPGs and the HB-EGF heparin-binding domain, and that disruption of this interaction leads to increased release of soluble ligand and a switch in cell phenotype from juxtacrine-induced growth inhibition to autocrine-induced proliferation. Our results indicate that extracellular HSPGs serve to sequester the transmembrane pro-form of HB-EGF at the point of cell-cell contact, and that this plays a role in governing the balance between juxtacrine versus autocrine and paracrine signaling.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1242/jcs.058321
