title: Calcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages.
abstract: Macropinocytosis can be induced in several cell types by stimulation with growth factors. In selected cell types, notably macrophages and dendritic cells, macropinocytosis occurs constitutively, supporting the uptake of antigens for subsequent presentation. Despite their different mode of initiation and contrasting physiological roles, it is tacitly assumed that both types of macropinocytosis are mechanistically identical. We report that constitutive macropinocytosis is stringently calcium dependent, while stimulus-induced macropinocytosis is not. Extracellular calcium is sensed by G-protein-coupled calcium-sensing receptors (CaSR) that signal macropinocytosis through Gα-, phosphatidylinositol 3-kinase and phospholipase C. These pathways promote the recruitment of exchange factors that stimulate Rac and/or Cdc42, driving actin-dependent formation of ruffles and macropinosomes. In addition, the heterologous expression of CaSR in HEK293 cells confers on them the ability to perform constitutive macropinocytosis. Finally, we show that CaSR-induced constitutive macropinocytosis facilitates the sentinel function of macrophages, promoting the efficient delivery of ligands to cytosolic pattern-recognition receptors.
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Canton
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schlam
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Breuer
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.affiliation: Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, Ontario, Canada M5G 1G6.
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, Canada M5G 0A4.|Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, 290 Victoria Street, Toronto, Ontario, Canada M5C 1N8.
authors.forename: Sergio
authors.initials: S
authors.lastname: Grinstein
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000166:cytology; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010873:Pinocytosis; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D008024:Ligands; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D044169:Receptors, Calcium-Sensing; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D002118:Calcium