Presentation Abstract

Session Title: PLATFORM H: Membrane Receptors & Signal Transduction I
Location: Room 307
Presentation Number: 111-Plat
Presentation Time: 3/6/2011 11:30:00 AM
Author Block: Khuloud Jaqaman1, Hirotaka Kuwata2, Nicolas Touret3, Richard Collins2, William S. Trimble2, Gaudenz Danuser1, Sergio Grinstein2.
1Harvard Medical School, Boston, MA, USA, 2Hospital for Sick Children, Toronto, ON, Canada, 3University of Alberta, Edmonton, AB, Canada.
Abstract Body: Receptor clustering and organization into membrane microdomains is an essential feature of transmembrane signal transduction. The processes that govern the coalescence of receptors into functional aggregates, however, are poorly understood.
CD36 is a clustering-responsive class B scavenger receptor in macrophages, where it binds to multivalent ligands such as oxidized low-density lipoprotein (oxLDL), apoptotic cells and malaria-infected erythrocytes. It is implicated in a wide range of processes, from lipid metabolism to innate immunity to tissue. Biochemical studies suggest that CD36 clustering at the cell surface upon engagement of multivalent ligands triggers signal transduction and receptor-ligand complex internalization. However, it is not known whether CD36 receptors at rest exist as monomers or as oligomers that facilitate the cellular response to ligand exposure, and what factors contribute to CD36 clustering.
To address these questions, we combined quantitative live-cell single-molecule imaging and biochemical approaches to study the dynamics, oligomerization and signaling of CD36 in primary human macrophages. We found that unliganded CD36 receptors exist in the membrane as metastable oligomers that prime the cells to respond to ligand exposure. Temporal multi-scale analysis of single receptor trajectories combined with pharmacological perturbation of the cytoskeleton showed that the movement of CD36 in the membrane was controlled by the submembranous actomyosin meshwork and by microtubules. Specifically, a subset of receptors diffused within cytoskeleton-dependent linear channels which promoted receptor oligomerization by allowing free diffusion in one direction while imposing confinement along the perpendicular direction. Perturbation of this organization markedly decreased CD36-mediated signal transduction. These data demonstrate a critical role for the cytoskeleton in controlling CD36 signaling by organizing the diffusion of receptors within regions of the membrane that increase receptor collision and oligomerization frequency.
Commercial Relationship:  K. Jaqaman: None. H. Kuwata: None. N. Touret: None. R. Collins: None. W.S. Trimble: None. G. Danuser: None. S. Grinstein: None.

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