Editors' ChoiceGrowth Factors

Being in the Membrane Matters

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Science's STKE  23 Mar 2004:
Vol. 2004, Issue 225, pp. tw106-TW106
DOI: 10.1126/stke.2252004TW106

Heparin-binding EGF (epidermal growth factor)-like growth factor (HB-EGF) is expressed in many epithelial cells. The growth factor is synthesized as a transmembrane protein (proHB-EGF), which can be released as a soluble growth factor when cleaved by metalloproteinase activity. The soluble growth factor binds to the EGF receptor 1 (EGFR1, also called erbB1) and the related erbB4 protein and promotes cell proliferation and migration. Less clear has been the role of membrane-bound proHB-EGF, which is proposed to participate in juxtacrine signaling and has been reported to both stimulate or inhibit cell proliferation and to protect from or induce cell death. Singh et al. attempted to clarify the roles of membrane-anchored and soluble HB-EGF by analyzing Madin-Darby canine kidney II cells stably transfected with either a mutant form of proHB-EGF that cannot be cleaved and thus functions solely in the membrane or a soluble form of HB-EGF with no membrane anchor. The soluble protein caused decreased cell adhesion and promoted cell migration in response to another growth factor, hepatocyte growth factor (HGF, also called scatter factor), whereas the membrane-anchored version inhibited cell migration and HGF-induced cell scattering and promoted cell adhesion. These distinct effects may reflect the fact that the actions of membrane-bound HB-EGF were not inhibited by pharmacological inhibition of EGF receptor tyrosine phosphorylation and, thus, may not be produced by juxtacrine signaling through the EGF receptor. Instead, proHB-EGF forms complexes with heparin sulfate proteoglycans and with other membrane proteins including the tetraspanin family member CD9. CD9 in turn interacts with α3β1 integrins. Blocking such interactions with antibody to CD9 or with heparinase relieved the inhibitory action of membrane-bound HB-EGF on cell motility. The authors suggest, therefore, that membrane-associated HB-EGF may act more as a scaffold protein in the membrane, where it may foster interaction of complexes of proteins that influence cell-cell interactions.

A. B. Singh, T. Tsukada, R. Zent, R. C. Harris, Membrane-associated HB-EGF modulates HGF-induced cellular responses in MDCK cells. J. Cell Sci. 117, 1365-1379 (2004). [Abstract] [Full Text]

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