title: Phosphatidic acid is required for the constitutive ruffling and macropinocytosis of phagocytes.
abstract: Macrophages and dendritic cells continuously survey their environment in search of foreign particles and soluble antigens. Such surveillance involves the ongoing extension of actin-rich protrusions and the consequent formation of phagosomes and macropinosomes. The signals inducing this constitutive cytoskeletal remodeling have not been defined. We report that, unlike nonphagocytic cells, macrophages and immature dendritic cells have elevated levels of phosphatidic acid (PA) in their plasma membrane. The plasmalemmal PA is synthesized by phosphorylation of diacylglycerol, which is in turn generated by a G protein-stimulated phospholipase C. Inhibition of diacylglycerol kinase activity results in the detachment of T-cell lymphoma invasion and metastasis-inducing protein 1 (TIAM1)-a Rac guanine exchange factor-from the plasma membrane, thereby depressing Rac activity and abolishing the constitutive ruffling and macropinocytosis that characterize macrophages and immature dendritic cells. Accumulation of PA and binding of TIAM1 to the membrane require the activity of phosphatidylinositol-4,5-bisphosphate 3-kinase. Thus a distinctive, constitutive pathway of PA biosynthesis promotes the actin remodeling required for immune surveillance.
authors.affiliation: Division of Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Michal
authors.initials: M
authors.lastname: Bohdanowicz
authors.forename: Daniel
authors.initials: D
authors.lastname: Schlam
authors.forename: Martin
authors.initials: M
authors.lastname: Hermansson
authors.forename: David
authors.initials: D
authors.lastname: Rizzuti
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Fairn
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ueyama
authors.forename: Pentti
authors.initials: P
authors.lastname: Somerharju
authors.forename: Guangwei
authors.initials: G
authors.lastname: Du
authors.forename: Sergio
authors.initials: S
authors.lastname: Grinstein
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D004075:Diglycerides / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007157:Immunologic Surveillance; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D010712:Phosphatidic Acids / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010873:Pinocytosis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D020662:Guanine Nucleotide Exchange Factors; D010712:Phosphatidic Acids; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D010738:Type C Phospholipases