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Plasma membrane domain organization regulates EGFR signaling in tumor cells

¹ Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
² Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
³ Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
⁴ Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada
⁵ Department of Medical Genetics and ⁶ Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario M5G 1L5, Canada

Correspondence to Ivan R. Nabi: ivan.robert.nabi{at}ubc.ca

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 ß1,6N-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 ß1,6GlcNAc-branched N-glycans are below a threshold for optimal galectin lattice formation.

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