Plasma membrane domain organization regulates EGFR signaling in tumor cells.
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.
Lajoie
Patrick
P
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Partridge
Emily A
EA
Guay
Ginette
G
Goetz
Jacky G
JG
Pawling
Judy
J
Lagana
Annick
A
Joshi
Bharat
B
Dennis
James W
JW
Nabi
Ivan R
IR
D000199:Actins / Q000378:metabolism; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D051242:Caveolin 1 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D003599:Cytoskeleton / Q000187:drug effects; D004058:Diffusion / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D037161:Galectins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053778:Thiazolidines / Q000494:pharmacology
D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051242:Caveolin 1; D037161:Galectins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D053778:Thiazolidines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C037067:latrunculin A