The heparin-binding domain of HB-EGF mediates localization to sites of cell-cell contact and prevents HB-EGF proteolytic release

Journal Article · Thu Jul 01 04:00:00 EDT 2010 · Journal of Cell Science, 123(13):2308-2318

DOI:https://doi.org/10.1242/jcs.058321· OSTI ID:988640

Prince, Robin N; Schreiter, Eric R; Zou, Peng; Wiley, H S; Ting, Alice Y; Lee, Richard T; Lauffenburger, Douglas A

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 EGFlike domain of HB-EGF and the cytoplasmic C-terminus. A striking observation was the absence of the HB-EGF transmembrane proform 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 HBEGF 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.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (US)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 988640
• Report Number(s): PNNL-SA-73406; KP1704020
• Journal Information: Journal of Cell Science, 123(13):2308-2318, Journal Name: Journal of Cell Science, 123(13):2308-2318 Journal Issue: 13 Vol. 123; ISSN 0021-9533; ISSN JNCSAI
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
Cell-cell contact
DIFFUSION
GROWTH
GROWTH FACTORS
Heparan-sulfate proteoglycan (HSPG)
Heparin binding
Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF)
INHIBITION
Juxtacrine
PHENOTYPE
PROLIFERATION
PROTEINS