RESEARCH ARTICLE


Membrane Regulation of EGFR Signaling by Gangliosides



Xiao-qi Wang, Amy S. Paller*
Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Department of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA


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© 2009 Wang and Paller

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N St. Clair, Suite 1600, Chicago, IL 60611-2997, USA; Tel: 312-695-3721; Fax: 312-695-0664; E-mail:apaller@northwestern.edu


Abstract

Signal transduction is initiated at the cell membrane by the interaction of membrane-anchored receptors (such as growth factors or integrin) with extracellular stimuli (ligands). The availability of these receptors for their ligands and how the activated receptors triggers intracellular signaling cascades are regulated, at least in part, by cholesterol and sphingolipids of the plasma membrane. Gangliosides, sialylated glycosphingolipids, were first shown to regulate epidermal growth factor receptor (EGFR) signal transduction at the membrane level of epithelial cells in the mid-1980’s. Since that time gangliosides have been shown to influence the signaling of a variety of other growth factor receptors. Regulation of signaling by gangliosides involves ganglioside-induced shifts of signaling components at the membrane level that either promote or disrupt signaling complexes. To decrease phosphorylation of the EGFR, ganglioside GM3 has been shown to promote the formation of a complex in which the caveolin-1 and tetraspanin CD82-dependent association of PKC-α with EGFR leads to increased threonine phosphorylation of the EGFR and EGFR internalization, making it unavailable for ligand stimulation. The lack of available EGFR at the membrane may also impact EGFR crosstalk with other signaling pathways, such as those triggered by activation of integrins and the urokinase-like plasminogen activator receptor.