title: Akt3 kinase suppresses pinocytosis of low-density lipoprotein by macrophages via a novel WNK/SGK1/Cdc42 protein pathway.
abstract: Fluid-phase pinocytosis of LDL by macrophages is regarded as a novel promising target to reduce macrophage cholesterol accumulation in atherosclerotic lesions. The mechanisms of regulation of fluid-phase pinocytosis in macrophages and, specifically, the role of Akt kinases are poorly understood. We have found previously that increased lipoprotein uptake via the receptor-independent process in Akt3 kinase-deficient macrophages contributes to increased atherosclerosis inAkt3-/-mice. The mechanism by which Akt3 deficiency promotes lipoprotein uptake in macrophages is unknown. We now report that Akt3 constitutively suppresses macropinocytosis in macrophages through a novel WNK1/SGK1/Cdc42 pathway. Mechanistic studies have demonstrated that the lack of Akt3 expression in murine and human macrophages results in increased expression of with-no-lysine kinase 1 (WNK1), which, in turn, leads to increased activity of serum and glucocorticoid-inducible kinase 1 (SGK1). SGK1 promotes expression of the Rho family GTPase Cdc42, a positive regulator of actin assembly, cell polarization, and pinocytosis. Individual suppression of WNK1 expression, SGK1, or Cdc42 activity in Akt3-deficient macrophages rescued the phenotype. These results demonstrate that Akt3 is a specific negative regulator of macropinocytosis in macrophages.
authors.affiliation: From the Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio 44195 and.
authors.forename: Liang
authors.initials: L
authors.lastname: Ding
authors.affiliation: From the Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio 44195 and.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: the Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Michael
authors.initials: M
authors.lastname: Kim
authors.affiliation: From the Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio 44195 and.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Byzova
authors.affiliation: From the Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio 44195 and podreze@ccf.org.
authors.forename: Eugene
authors.initials: E
authors.lastname: Podrez
mesh_terms: D000818:Animals; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D010873:Pinocytosis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000076204:WNK Lysine-Deficient Protein Kinase 1; D020764:cdc42 GTP-Binding Protein; D000099184:Serum-Glucocorticoid Regulated Kinases; C581598:Cdc42 protein, mouse; C491754:AKT3 protein, human; C491753:Akt3 protein, mouse; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse
keywords: Akt PKB; LDL; atherosclerosis; endocytosis; macrophage; small GTPase