Abstract
Abstract Expression of MS4A family proteins influence the cell cycle and may be involved in tumorigenesis. However, the mechanistic basis for these observations remains elusive. We have identified roles for a member of the MS4A family, FcεRIβ (MS4A2), in protein trafficking and signal transduction in human mast cells (Immunity, 38, p906, 2013) and predicted analogous roles for other MS4A proteins. Employing mast cells, we found that down-regulation of MS4A4 reduced KIT expression (the receptor for SCF), and contributed to effector functions. MS4A4 “stabilized” surface KIT by slowing KIT internalization kinetics in response to SCF. Our data suggest that the mechanism for this action may involve trafficking of KIT by MS4A4 from sorting early endosomes to the endocytic recycling center, diverting receptors away from late endosome-dependent ERK kinase signaling and receptor degradation. Thus, in this instance, gene-silencing of MS4A4 reduced recycling pathways resulting in enlarged EEA1+ early endosomes, prolonged ERK signaling, and increased KIT progression to Rab9+ late endosomes. Therefore, MS4A4 appears to promote mast cell maturation by altering the endocytic trafficking and localization of KIT signaling, fine tuning effector functions. Our proposed function of MS4A4 in KIT trafficking is similar to the role that FcεRIβ plays in FcεRI trafficking and raises the question of whether other MS4A gene family members similarly regulate trafficking of receptors and associated molecules.
Published Version
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