TNF-alphaのシグナリング

Tumor necrosis factor

http://www.uniprot.org/uniprot/P01375
GeneTNF
TNFRSF1A/TNFR1と結合するサイトカイン。主にマクロファージが分泌し、ある種の腫瘍細胞に細胞死をもたらす。直接、又はIL-1の分泌を経由してはたらく発熱因子で、悪液質の発生に関与する。ある条件下で細胞の分裂や分化を促す。
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.1 Publication
The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.
Tumor necrosis factor
Alternative name(s):
Cachectin
TNF-alpha
Tumor necrosis factor ligand superfamily member 2
Short name:
TNF-a
Cleaved into the following 6 chains:
Tumor necrosis factor, membrane form
Alternative name(s):
N-terminal fragment
Short name:
NTF
Intracellular domain 1
Short name:
ICD1
Intracellular domain 2
Short name:
ICD2
C-domain 1
C-domain 2
Tumor necrosis factor, soluble form
Post-translational modificationi
The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space.3 Publications
The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1.2 Publications
O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid.
Subunit structurei
Homotrimer. Interacts with SPPL2B.

Tumor necrosis factor receptor superfamily member 1B

GeneTNFRSF1B
http://www.uniprot.org/uniprot/P20333
TNFSF2/TNF-alphaに高い親和性(TNFSF1/lymphotoxin-alphaに比べて5倍)をもつ。TRAF1/TRAF2複合体が加わり、アポトーシス抑制因子(BIRC2/3)がTNFRSF1B/TNFR2に変換される。この受容体がTNF-αのほとんどの代謝効果を仲介している。アイソフォーム2(C末端側約200アミノ酸が欠失)はTNF-αの作用に拮抗的に働く。
Receptor with high affinity for TNFSF2/TNF-alpha and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This receptor mediates most of the metabolic effects of TNF-alpha. Isoform 2 blocks TNF-alpha-induced apoptosis, which suggests that it regulates TNF-alpha function by antagonizing its biological activity.
Alternative name(s):
Tumor necrosis factor receptor 2
Short name:
TNF-R2
Tumor necrosis factor receptor type II
Short name:
TNF-RII
Short name:
TNFR-II
p75
p80 TNF-alpha receptor
CD_antigen: CD120b
INN: Etanercept
Cleaved into the following 2 chains:
Tumor necrosis factor receptor superfamily member 1b, membrane form
Tumor necrosis factor-binding protein 2
Alternative name(s):
TBP-2
TBPII
Pharmaceutical usei
Available under the name Enbrel (Immunex and Wyeth-Ayerst). Used to treat moderate to severe rheumatoid arthritis (RA). Enbrel consist of the extracellular ligand-binding portion of TNFRSF1B linked to an immunoglobulin Fc chain. It binds to TNF-alpha and blocks its interactions with receptors.
Post-translational modificationi
Phosphorylated; mainly on serine residues and with a very low level on threonine residues.
A soluble form (tumor necrosis factor binding protein 2) is produced from the membrane form by proteolytic processing.
Subunit structurei
Binds to TRAF2. Interacts with BMX.

TNF receptor-associated factor 2

TNF受容体関連因子2
http://www.uniprot.org/uniprot/Q12933
GeneTRAF2
NFkBやJNKの活性を制御し、細胞の生存やアポトーシスの調節に中心的役割をもつ。BRIC3,RIPK1,TICAM1などを標的とするユビキチンリガーゼ活性をもち、交替のIgMからIgGへのクラススイッチに関与する。
活性調節
スフィンゴシン1-リン酸の存在下で強く活性化される。
翻訳後修飾
多くのセリン残基がリン酸化される。117番目のトレオニンのリン酸化がTNF and TNFRSF1Aのシグナリングに重要で、Lys-63ポリユビキチン化に必須である。また、IKKとそれを介するNF-KBの活性化につながるIKKA,IKKBとの相互作用にも重要である。(63Lysのユビキチン化はTRAF2によるNF−kBの活性化によりTNFシグナルを伝え、48Lysのポリユビキチン化はプロテアソームによる分解につながる。
Regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Required for normal antibody isotype switching from IgM to IgG. Has E3 ubiquitin-protein ligase activity and promotes 'Lys-63'-linked ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases. Regulates BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination and subsequent degradation; this does not depend on the TRAF2 RING-type zinc finger domain. Plays a role in mediating activation of NF-kappa-B by EIF2AK2/PKR. In complex with BIRC2 or BIRC3, promotes ubiquitination of IKBKE.
Enzyme regulation
Has very low E3 ubiquitin ligase activity in the absence of sphingosine-1-phosphate. E3 ubiquitin ligase activity is strongly activated by cytoplasmic sphingosine-1-phosphate.
Post-translational modification
Phosphorylated at several serine residues within the first 128 amino acid residues. Phosphorylated at Thr-117 in response to signaling via TNF and TNFRSF1A. Phosphorylation at Thr-117 is required for 'Lys-63'-linked polyubiquitination, but not for 'Lys-48'-linked polyubiquitination. Phosphorylation at Thr-117 is important for interaction with IKKA and IKKB, activation of IKK and subsequent activation of NF-kappa-B.
Undergoes both 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination. Polyubiquitinated via 'Lys-63'-linked ubiquitin in response to TNF signaling; this requires prior phosphorylation at Thr-117. 'Lys-63'-linked polyubiquitination promotes TRAF2-mediated activation of NF-kappa-B. Can be polyubiquitinated at several Lys residues via 'Lys-48'-linked ubiquitin chains in response to TNF signaling, leading to proteasomal degradation. Autoubiquitinated, leading to its subsequent proteasomal degradation. Polyubiquitinated by BIRC2 and SIAH2, leading to its subsequent proteasomal degradation. Deubiquitinated by CYLD, a protease that specifically cleaves 'Lys-63'-linked polyubiquitin chains.

Tumor necrosis factor receptor type 1-associated DEATH domain protein

GeneTRADD
http://www.uniprot.org/uniprot/Q15628
核移行型で、腫瘍抑制因子として働く。
TNF受容体
The nuclear form acts as a tumor suppressor by preventing ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A by TRIP12: acts by interacting with TRIP12, leading to disrupt interaction between TRIP12 and isoform p19ARF/ARF of CDKN2A (By similarity). Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa-B.