title: The CD20 homologue MS4A4 directs trafficking of KIT toward clathrin-independent endocytosis pathways and thus regulates receptor signaling and recycling.
abstract: MS4A family members differentially regulate the cell cycle, and aberrant, or loss of, expression of MS4A family proteins has been observed in colon and lung cancer. However, the precise functions of MS4A family proteins and their mechanistic interactions remain unsolved. Here we report that MS4A4 facilitates trafficking of the receptor tyrosine kinase KIT through endocytic recycling rather than degradation pathways by a mechanism that involves recruitment of KIT to caveolin-1-enriched microdomains. Silencing of MS4A4 in human mast cells altered ligand-induced KIT endocytosis pathways and reduced receptor recycling to the cell surface, thus promoting KIT signaling in the endosomes while reducing that in the plasma membrane, as exemplified by Akt and PLCγ1 phosphorylation, respectively. The altered endocytic trafficking of KIT also resulted in an increase in SCF-induced mast cell proliferation and migration, which may reflect altered signaling in these cells. Our data reveal a novel function for MS4A family proteins in regulating trafficking and signaling, which could have implications in both proliferative and immunological diseases.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 glenncruse@hotmail.com.
authors.forename: Glenn
authors.initials: G
authors.lastname: Cruse
authors.affiliation: Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Music
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
mesh_terms: D018951:Antigens, CD20 / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008407:Mast Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D018951:Antigens, CD20; D002966:Clathrin; C424714:MS4A4A protein, human; D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit; D051966:Phospholipase C gamma; C427755:RAB5C protein, human; D020696:rab5 GTP-Binding Proteins