Plasma membrane domain organization regulates EGFR signaling in tumor cells.

Abstract

Macromolecular complexes exhibit reduced diffusion in biological membranes; however, the physiological consequences of this characteristic of plasma membrane domain organization remain elusive. We report that competition between the galectin lattice and oligomerized caveolin-1 microdomains for epidermal growth factor (EGF) receptor (EGFR) recruitment regulates EGFR signaling in tumor cells. In mammary tumor cells deficient for Golgi beta1,6N-acetylglucosaminyltransferase V (Mgat5), a reduction in EGFR binding to the galectin lattice allows an increased association with stable caveolin-1 cell surface microdomains that suppresses EGFR signaling. Depletion of caveolin-1 enhances EGFR diffusion, responsiveness to EGF, and relieves Mgat5 deficiency-imposed restrictions on tumor cell growth. In Mgat5(+/+) tumor cells, EGFR association with the galectin lattice reduces first-order EGFR diffusion rates and promotes receptor interaction with the actin cytoskeleton. Importantly, EGFR association with the lattice opposes sequestration by caveolin-1, overriding its negative regulation of EGFR diffusion and signaling. Therefore, caveolin-1 is a conditional tumor suppressor whose loss is advantageous when beta1,6GlcNAc-branched N-glycans are below a threshold for optimal galectin lattice formation.

• Authors: Patrick Lajoie, Emily A Partridge, Ginette Guay, Jacky G Goetz, Judy Pawling, Annick Lagana, Bharat Joshi, James W Dennis, Ivan R Nabi
• Journal: The Journal of cell biology (J Cell Biol) Vol. 179 Issue 2 Pg. 341-56 (Oct 22 2007) ISSN: 0021-9525 [Print] United States
• PMID: 17938246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Bridged Bicyclo Compounds, Heterocyclic
• Caveolin 1
• Galectins
• Nerve Tissue Proteins
• Recombinant Fusion Proteins
• Thiazolidines
• Epidermal Growth Factor
• ErbB Receptors
• latrunculin A

Topics

• Actins (metabolism)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Caveolin 1 (metabolism)
• Cell Membrane (drug effects, enzymology)
• Cytoskeleton (drug effects)
• Diffusion (drug effects)
• Embryonic Stem Cells (drug effects, enzymology)
• Enzyme Activation (drug effects)
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (chemistry, metabolism)
• Fluorescence Recovery After Photobleaching
• Galectins (metabolism)
• Mice
• Models, Biological
• Neoplasms (pathology)
• Nerve Tissue Proteins (metabolism)
• Phosphorylation (drug effects)
• Protein Structure, Tertiary
• Protein Transport (drug effects)
• Recombinant Fusion Proteins (metabolism)
• Signal Transduction (drug effects)
• Thiazolidines (pharmacology)