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 beta 1,6N- 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 beta 1,6GlcNAc- branched N-glycans are below a threshold for optimal galectin lattice formation.