title: Delivery of CSF-1R to the lumen of macropinosomes promotes its destruction in macrophages.
abstract: Activation of the macrophage colony stimulating factor-1 receptor (CSF-1R) by CSF-1 stimulates pronounced macropinocytosis and drives proliferation of macrophages. Although the role of macropinocytosis in CSF-1R signaling remains unknown, we show here that, despite internalizing large quantities of plasma membrane, macropinosomes contribute little to the internalization of the CSF-1-CSF-1R complex. Rather, internalization of the CSF-1R in small endocytic vesicles that are sensitive to clathrin disruption, outcompetes macropinosomes for CSF-1R endocytosis. Following internalization, small vesicles carrying the CSF-1R underwent homotypic fusion and then trafficked to newly formed macropinosomes bearing Rab5. As these macropinosomes matured, acquiring Rab7, the CSF-1R was transported into their lumen and degraded. Inhibition of macropinocytosis delayed receptor degradation despite no disruption to CSF-1R endocytosis. These data indicate that CSF-1-stimulated macropinosomes are sites of multivesicular body formation and accelerate CSF-1R degradation. Furthermore, we demonstrate that macropinocytosis and cell growth have a matching dose dependence on CSF-1, suggesting that macropinosomes might be a central mechanism coupling CSF-1R signaling and macrophage growth.
authors.affiliation: Department of Chemistry and Biochemistry, South Dakota State University, Brookings, 57007 SD, USA.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Chemistry and Biochemistry, South Dakota State University, Brookings, 57007 SD, USA.
authors.forename: Shalini T
authors.initials: ST
authors.lastname: Low-Nam
authors.affiliation: Department of Chemistry and Biochemistry, South Dakota State University, Brookings, 57007 SD, USA.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Kerkvliet
authors.affiliation: Department of Chemistry and Biochemistry, South Dakota State University, Brookings, 57007 SD, USA adam.hoppe@sdstate.edu.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Hoppe
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology; D008954:Models, Biological; D010873:Pinocytosis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D002966:Clathrin; D008934:Mitogens; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins
keywords: CSF-1R; Endocytosis; M-CSF; Macrophage; Macropinosome