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单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Intracellular Accumulation of Lipids via Scavenger Receptors,Qi Chen,Nanjing Medical University,2005.8,Intracellular Accumulation of,1,Formation of foam cell,Athersclerosis is a chronic inflammatory reaction caused by macrophages and lymphocytes that uptake the pathogenicity lipids invading the vessel.,Formation of foam cell Athe,2,SR-A and CD36 are the principal receptors responsible for foam-cell formation,Macrophage cell takes up lipid by SR-A,SR-A and CD36 are the principa,3,Structure of SR-A,Six domains,Three types,Trimeric molecule,Structure of SR-A Six doma,4,Foam cell formation,M adhesion,Host defense and innate,immunity,Adaptive responses,Disorders of the nervous,system,Phagocytosis of apoptotic,cells,Functions of SR-A,Foam cell formationFunctions,5,The cytoplasmic domain is the key part of the receptor,The cytoplasmic domain is the,6,mediate the internalization of ligands such as ox-LDL,participate the regulation of cell adhesion and migration,accommodate the expression and transport of receptor,link-coupled with downstream of signaling pathway,Functions of SR-A cytoplasmic domain:,mediate the internalization o,7,Cytoplasmic domain：,Murine:MTKEMTENQRLCPHEREDADCSSES,VKFDARS,MTA,SL,P,HSTKNGPSVQE,KLKSFK,(55),Rabbit:MAQWDSFTDQQEDTDSCSES,VKFDARS,NTA,LL,PPNPK,GPPLQE,KLKSFK,(,50,),Bovine:MAQWDDFPDQQEDTDSCTES,VKFDARS,VTA,LL,PPHPKN,GPTLQERMKSYK,(50),Human:MEQWDHFHNQQEDTDSCSES,VKFDARS,MTA,LL,PPNPK,NSPSLQE,KLKSFK,(50),Cytoplasmic domain：,8,MSR-A,AcLDL,HSP90,HSP70,and GAPDH Directly Interact with the Cytoplasmic Domain of MSR,Nakamura T.et al.BBRC,290,858-864(2002),Functional and possible physical association of scavenger receptor with cytoplasmic tyrosine kinase Lyn in monocytic THP-l-derived Macrophages,Miki S.et al.FEBS Letters,399,241-244(1996),HSP90 HSP70 GAPDH,Lyn,MSR-AAcLDLHSP90,HSP70,and GA,9,Ligand Binding to Macrophage Scavenger Receptor-A Induces Urokinase-type Plasminogen Activator Expression,by a Protein Kinase-dependent Signaling Pathway,Hsien-Yeh Hsu et al.J Biol Chem,273,1240-1246(1998),MSR-A,AcLDL,Fucoidan,PTK,PLC-,PKC,uPA,Ligand Binding to Macrophage S,10,MSR-A,Fucoidan,Hsp90,pp60Src,Rac1,PAK,JNK,p38,PI3K,proIL-1,IL-1,Ligands of Macrophage Scavenger Receptor Induce Cytokine Expression via,Differential Modulation of Protein Kinase Signaling Pathways,Hsu HY.et al.J Biol Chem,276,28719-28730(2001),MSR-AFucoidanHsp90,pp60SrcRac1,11,MSR-A,AcLDL,internalization,adhesion,Gi/o,Regulation of acetylated low density lipoprotein uptake in macrophages by pertussis toxin-sensitive G proteins,Stewart C et al.J Lipid Res,41,807-813(2000),Class A scavenger receptors mediate cell adhesionvia activation of Gi/o and formation of focal adhesion complexes,Post SR.et al.J Lipid Res,43,1829-1836(2002),MSR-AAcLDLinternalization,adh,12,phosphorylation of cytoplasmic domain,signal sequence in cytoplasmic domain,interactors with cytoplasmic domain,Focus on cytoplasmic domain：,phosphorylation of cytoplasm,13,Bovine Model,Human Model,Murine Model,Rabbit Model,Bovine ModelHuman ModelMurine,14,Ser21（rat）,increases expression of receptor,promotes metabolism of lipid,Fong LG et al.,J Biol Chem,274,36088-36816(1999),phosphorylation of cytoplasmic domain,Ser21（rat）phosphorylation of c,15,phosphorylation of cytoplasmic domain,Ser49（rat）,reduces uptake of lipid,Fong LG et al.,J Biol Chem,274,36088-36816(1999),phosphorylation of cytoplasmic,16,FDARS,internalization of receptor,Fong LG et al.,J Biol Chem,274,36088-36816(1999),signal sequence of cytoplasmic domain,FDARS signal sequence of cyto,17,KLKSFK,cell adhesion,Kosswig N et al.J Biol Chem,278,34219-34225(2003),signal sequence of cytoplasmic domain,KLKSFK signal sequence of cyto,18,VXFD(rabbit),internalization of receptor,transference to cell surface,Morimoto K et al.Biol Pharm Bull,22,1022-1026(1999),signal sequence of cytoplasmic domain,VXFD(rabbit)signal sequence o,19,Ser48(human）,expression and,internalization,of receptor,cell migration,Heider H et al.FEBS Letters,505,185-190(2001),phosphorylation of cytoplasmic domain,Ser48(human）phosphorylation o,20,Di-leucine motif?,signal sequence of cytoplasmic domain,Di-leucine motif?signal seque,21,1.The role of Di-leucine motif in the cytoplasmic domain of SRA,1.The role of Di-leucine mot,22,(1)SR-A mutants/EGFP constructs:,Wild type,N3132LM,EGFP,SRA,SRA,(1)SR-A mutants/EGFP construc,23,(2)Expression patterns of SRA mutant:,*P0.05,n=3,EGFP,SR-A N3132LM,EGFP,SR-A,N3132LM,*,0,200,400,600,800,1000,control,EGFP,SR-A,N3132LM,(2)Expression patterns of SRA,24,(3)The internalization of DiI-AcLDL via SRA mutant:,DiI-acLDL,SR-A expression,*,*,DiI-acLDL,*P0.05,n=3,*,*P0.05,n=3,0,10,20,30,40,EGFP,Wild type,N3132LM,*,EGFP,Wild type,N3132LM,0.02,0.04,0.06,0.08,0.10,0.12,(3)The internalization of DiI,25,(4)Cell adhesion via SRA mutant:,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,EGFP,SR-A,N3132LM,ratio,%,*,*,P0.05,n=3,*,(4)Cell adhesion via SRA muta,26,EGFP,SR-A,N31
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