dc.contributor.author | Prince, Robin N. | |
dc.contributor.author | Schreiter, Eric R. | |
dc.contributor.author | Zou, Peng | |
dc.contributor.author | Wiley, H. Steven | |
dc.contributor.author | Ting, Alice Y. | |
dc.contributor.author | Lee, Richard T. | |
dc.contributor.author | Lauffenburger, Douglas A. | |
dc.date.accessioned | 2012-10-16T14:46:27Z | |
dc.date.available | 2012-10-16T14:46:27Z | |
dc.date.issued | 2010-06 | |
dc.identifier.issn | 0021-9533 | |
dc.identifier.issn | 1477-9137 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/74015 | |
dc.description.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. | en_US |
dc.description.sponsorship | National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant EB003805) | en_US |
dc.description.sponsorship | National Cancer Institute (U.S.) (Grant CA96504) | en_US |
dc.description.sponsorship | Massachusetts Institute of Technology. Poitras Pre-Doctoral Fellowship | en_US |
dc.description.sponsorship | National Science Foundation (U.S.). Graduate Research Fellowship Program | en_US |
dc.language.iso | en_US | |
dc.publisher | Company of Biologists, The | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1242/jcs.058321 | en_US |
dc.rights | Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. | en_US |
dc.source | Prof. Lauffenburger | en_US |
dc.title | The heparin-binding domain of HB-EGF mediates localization to sites of cell-cell contact and prevents HB-EGF proteolytic release | en_US |
dc.type | Article | en_US |
dc.identifier.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 | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biological Engineering | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Chemistry | en_US |
dc.contributor.approver | Lauffenburger, Douglas A | |
dc.contributor.mitauthor | Prince, Robin N. | |
dc.contributor.mitauthor | Zou, Peng | |
dc.contributor.mitauthor | Ting, Alice Y. | |
dc.contributor.mitauthor | Lauffenburger, Douglas A. | |
dc.relation.journal | Journal of Cell Science | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dspace.orderedauthors | Prince, R. N.; Schreiter, E. R.; Zou, P.; Wiley, H. S.; Ting, A. Y.; Lee, R. T.; Lauffenburger, D. A. | en |
dc.identifier.orcid | https://orcid.org/0000-0002-8277-5226 | |
dc.identifier.orcid | https://orcid.org/0000-0001-5319-3860 | |
mit.license | PUBLISHER_POLICY | en_US |
mit.metadata.status | Complete | |