Glia maturation factor-gamma modulation of signaling pathways in macrophages

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Leukocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle. Glia maturation factor-γ (GMFG), a novel regulator of the Arp2/3 complex, has been shown to be required for efficient directional migration of neutrophils and T-lymphocytes. Here, we investigated whether GMFG has similar effects on human monocyte migration, as well as the cellular mechanisms involved in GMFG action. We found that GMFG localizes to early endosomes (where it colocalizes with β1-integrins) and late endosomes, as well as the endocytic recycling compartment. Knockdown of GMFG in monocytes retarded the efficient rapid recycling of β1-integrins back to the plasma membrane and dramatically increased their degradation in both resting as well as fMLF- or SDF-1α-stimulated monocytes. Importantly, knockdown of GMFG results in reduced cell adhesion, and impaired directional migration of monocytes toward the chemoattractants fMLF and SDF-1α. These data identify GMFG as a molecular switch controlling β1-integrin recycling and its degradation to promote efficient monocyte migration.