Chinese Journal of Biochemistry and Molecular Biology . TNF. TNFR1 TNFR2. , HOU Gan, HUANG Di2Nan

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1 ISSN CN ΠQ Chinese Journal of Biochemistry and Molecular Biology 23 (6) : TNF2 3,, (, ) (tumor necrosis factor2alpha,tnf2 ) TNF 2 TNF ( TNFR), caspase TRAF NF2 B JNK TNFR1 TNFR2, 3, TNF 3, IKK RIP TRAF2 TRUSS (TNF2 ) ;TNF (TNFR) ;NF2 B ;JNK; Q74 Molecular Mechanism of TNF2 Signal Transduction QIU Chuang2Hua 3, HOU Gan, HUANG Di2Nan ( Department of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang , Guangdong, China) Abstract Tumor necrosis factor(tnf)2alpha is a pleiotropic cytokine,which exerts its biological functions by interactions with two members of the TNF receptor ( TNFR) Both receptors trigger several signal transduction pathways,including apoptosis mediated by caspase family, the activation of NF2 B and JNK mediated by scaffolding protein TRAF TNFR1 and TNFR2 perform their functions in a cooperative rather than independent manner There are various regulation mechanisms existing in the three signal transduction pathways, which contributes to the coordinative effect of TNF2 This article reviews the current progress on the studies of these signal transduction pathways, as well as the critical kinases and involved mechanism of action on the whole signal network, such as the activation of IKK, and the structure and interactive mold of some important signal molecules RIP, TRAF2 and TRUSS Key words tumor necrosis factor2alpha (TNF2 ) ; TNFR ; NF2 B ; JNK; apoptosis (tumor necrosis factor2alpha,tnf2 ) Π, Cys 2, TNF2 TNF2,, TNF2 TNF2, : , : TNF2, TNF2 TNF2 1 TNF (No No ) 3 Tel : (0759) ,E2mail com Received : November 16,2006 ; Accepted : February 2, 2007 Supported by Natural Science Foundation of , No ) 1 1 TNF2 TNF2,, 2 3 Corresponding author Tel : (0759) E2mail com Guangdong Province ( No China Academic Journal Electronic Publishing House All rights reserved

2 6 :TNF2 431, (2) TNFR12TRADD2TRAF( TNF receptor2associated, N C,N factors) NF2 B, TRADD DD RIP, TNF2 (reportor interacting protein) NF2 B, NF2 B, X :,Harper [2 ] TNF caspase28 Micheau [3 ], TNFR1 TNF2 Yan [1 ] TNF2 N 7, Pro82 Ser92Asp10 Arg2Lys2Arg Phe, NF2 B, Leu157, TNF2 L929 TRAF2 RIP 1 h TNFR1,, LD TRADD DD FADD, 1 2 TNF2 TNF 2 :TNFR1 TNFR2, TNFR2 DD, TNF TNFR1, ( TRAF),TNFR2 TRAF 426, 55 ku, TNF NF2kB JNK,, K d = pmolπl,, Till [4 ] TNFR2 180 min TNFR2, Met196 Arg, TNFR2 TRAF2 439, 75 ku, K d = pmolπl, 10 min TNFR1 TNFR2 (cysteine2 2 1 TNFR1, TNFR1 ( death domain, DD) TNFR1, TNFR1,NF2 B TRAF2 Π [6 TNF2 TNFR1 ], TNFR1, SODD 3 TNF,TNFR1 TRADD ( TRADD2associated death domain protein, TRADD), 2 :, NF2 B 2 (1) TNFR12TRADD2FADD FLICE ( FADD2like ICE) ΠMACH ( MORT12associated CED23, TNFR1 FADD : TNF, TNFR1 TRADD TRAF2 RIP caspase28,, 2 2 TNFR2 NF2 B ciap, TNFR1 TNFR2 rich2domain,crd), CRD 6, TNFR2, 3 CRD TNF TNFR1, TNFR1, TNF CRD2 TNFR2, CRD3 CRD1 CRD4 TNF TNF, TNFR1,, TNF, TNFR2 TRAF2 [ %, TNFR1 ], 2 TNFR2, TRAF2, NF2 B, 2 TNF ;, TRAF2 TNFR1 TNF,TNFR1 NF2 B TRAF1ΠTRAF2ΠcIAP1Π ( silencer of death domain,sodd) ciap2 caspase28, 3 1 NF2 B, 5 :NF2 B1 ( p105 p50), NF2 B2 ( p100 p52), RelA (p65), RelB c2 homolog)πcaspase28, caspase23, ; Rel NF2 B p65 p China Academic Journal Electronic Publishing House All rights reserved

3 NF2 B Rel RHR(rel homology region),, DNA [12 ] I B, RHR ( nuclear, localization signal,nls), NF2 B IKK PKBΠAkt IKK TNF,NF2 B, IKK IkB I B, NF2 B NLS, [13 ] Hu [14 ],NIBP (NIK NF2 B I B and IKK binding proein ) NIK ( NF2 B2inducing I B I B I B, 6 7 kinase,) IKK, IKK IKK,I B NF2, NIBP IKK I B B RHR TNF IKK I B p65, NIBP Ser32 Ser36 I B Ser19 Ser23 IKK Ea [15 ],TIFA ( TRAF2interacting, I B I B protein with a forkhead2associated domain), I B I B Lys21 Lys22, S26, NF2 IKK, B NLS, PKC NIK MEKK3 TAK1 RIP MAP3K, NF2 B, IKK,NF2 B I B, IKK [7 Π ],, I B, IKK : : IKK NIK p100 IKK, RIP NIK IKK, SCF TrCP, p100, IKK, p52 [9 ] Akt1 Akt2 ; (2) IKK ; (3) p100, HEK IKK, Akt ( PKB, B) p52 [10 ] Schwabe [11 ],IKK p65 IKK, S536 S468, IkB2p p65, IkB IKK( IkB kinase), IKK p65 IKK 2 IKK IKK FADD N IKK ΠNEMO (NF2 B essential modulator) IKK IKK SerΠTrp,IKK, MACHΠFLICE (caspase28) caspase28 IKK IKK, caspase23,6,7, : IKK IKK NF2 B B, IKK IKK PKBΠAkt TRAF6 IKK [8 SCF TrCP ], (1) IKK IKK IKK 2IKK, TNFR1 TRADD DD FADD C DD, FADD TNFR1 (DED), caspase, IKK IKK NF2 Caspase22 RAIDD DD RIP B IKK IKK, N ICH21, N caspase caspase23, RIP TNFR1, RAIDD caspase23 ICH21,, IKK RAIDD 2Π2,RAIDD TNF p100, IKK, PIDD (p532induced protein with a death domain), IKK I B, RAIDD [16 ] c2iap IKK, NF2 caspase23 caspase27, ; China Academic Journal Electronic Publishing House All rights reserved

4 6 :TNF2 433 [21 caspase26 caspase29 FLICE JNK ] (FLIP) 2 DED Papa [22 ], GADD45 ( growth arrest DNA caspase, caspase28 damage2inducible gene 45 ) MKK7 ATP FADD caspase28 Lys149, ATP MKK7, FLICE ( FLIP) TNF caspase ,TNF GADD45, c2flip L caspase28,c2flip L TNF JNK [17 ] caspase28,, [23 ] c2flip L CD8 + T, c2flip L caspase28, caspase28 c2flip L, RIP NF2 B [18 ] 4 1 RIP Kang RIP SerΠThr, C [19 ],caspase28, caspase28,rip NF2 B, Blonska [24 ],MEKK3 RIP, caspase28 IKK, IKK MEKK3 MEFs NF2 B RIP, 3 3 JNK MEKK3 TNFR1 NF2 B JNK 3 :,TAK1 NF2 B MAPKKK S MAPKK S MAPK S TRAF2 TAK1 TAB2, TNF MAPKKK S ( mitogen2activated protein kinase kinase kinase), MAPKKK S MKK4,MKK7 (MAPΠERK ) JNK(C2Jun N2terminal kinase) JNK (TAK12DD) MEKK RIP MKK4 MKK7 JNK Thr183 (MEKK32DD), RIP Tyr185 MKK4 Tyr185, JNK P38,MKK7 Thr183, JNK TGF2 1 TNFR1 [25 ] RIP TNFRI (TGF2 2activated kinase 1, TAK21) MKK4, TRADD FADD,RIP TNFR1 MKK7 JNK JNK c2jun, RIP TRADD TNFR1 Ser63 Ser73, Jun Fos RIP, ;, FADD TRADD [26 AP21,, ] 1 (ASK21) MAPKKK S 4 2 TRAF2,ASK1 MKK4 MKK3,6,TRAF2 TNF,ASK1 N, TNFR1 NF2 B JNK Trx TNF, ( N ROS,ROS Trx 2 Cys ) TRAF2 TNFR1 NF2 B, Trx, ASK1, ASK1 Thr2845 ASK1 C TRAF2, Huaer [27 ],TRAF2Π5 NF2, JNK P38 [20 ],ROS B, TRAF6 NF2 B MKPs (MAP kinase phosphatases) Cys MKK7, GADD45 (MEFs) JNK TNF TNF GADD45 4 DD,N, NF2 B,TAB2 RIP, TAK1 RIP TNFR1 TAK1 RIP,2 NF2 B, RIP, TRAF2,IKK IKK TNFR1 TRAF,, TRAF3 NIK, MKPs, JNK, NIK, TRAF2Π China Academic Journal Electronic Publishing House All rights reserved

5 NF2 B TNFR1 2 TNFR1, : NF2 B TNFR ;, TRUSS caspase TRAF2 TNFR1 : TRAF2 NF2 B NF2 B ; ciap1 ciap2 TRAF1 A20, TRAF2 caspase TRAF2 1 (ASK21) TAK2 TRUSS,TRUSS TRAF2 1 MEKK21, c2jun AP21, JNK, TRAF2 C TNF JNK traf2 2Π2 TRUSS JNK AP21, [28, ] TRUSS TNF2 AP21, 4 3 TRUSS Soond [29 ], TRUSS ( TNF2R2associated ubiquitous scaffolding and signaling protein ), 797,C ( ), DD, NF2 B, TRAF2 RIP, TRAF2 RIP TRUSS NF2 B, TRUSS TRUSS TRAF2 JNK [30 ] TRUSS 5 10, TNF TNFR1 DD,,Fig11 TNF TNFR1 IKK, :,, JNK,NF2 B,caspase, TRUSS N 1 440, Fig 1 TNF signal transduction pathways China Academic Journal Electronic Publishing House All rights reserved

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