Gene interactions and pathways from curated databases and text-mining
Mol Endocrinol 2006, PMID: 16543409

Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex.

Frobøse, Helle; Rønn, Sif Groth; Heding, Peter E; Mendoza, Heidi; Cohen, Philip; Mandrup-Poulsen, Thomas; Billestrup, Nils

IL-1 plays a major role in inflammation and autoimmunity through activation of nuclear factor kappa B (NFkappaB) and MAPKs. Although a great deal is known about the mechanism of activation of NFkappaB and MAPKs by IL-1, much less is known about the down-regulation of this pathway. Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown. We show here that SOCS-3 inhibits NFkappaB-dependent transcription induced by overexpression of the upstream IL-1 signaling molecules MyD88, IL-1R-activated kinase 1, TNF receptor-associated factor (TRAF)6, and TGFbeta-activated kinase (TAK)1, but not when the MAP3K MAPK/ERK kinase kinase-1 is used instead of TAK1, indicating that the target for SOCS-3 is the TRAF6/TAK1 signaling complex. By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6. Furthermore, SOCS-3 inhibited the IL-1-induced catalytic activity of TAK1. Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS-3 inhibited ubiquitin modification of TRAF6. These results indicate that SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1.

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Text Mining Data

interleukin-1 ⊣ TRAF-6/TAK1: " Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex "

interleukin-1 ⊣ TRAF-6/TAK1 complex: " Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex "

interleukin-1 ⊣ Suppressor of cytokine Signaling-3: " Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex "

IL-1 → NFkappaB: " Although a great deal is known about the mechanism of activation of NFkappaB and MAPKs by IL-1 , much less is known about the down-regulation of this pathway "

p38 ⊣ (SOCS)-3: " Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1 induced transcription and activation of NFkappaB and the MAPKs JNK and p38 , but the mechanism is unknown "

p38 ⊣ Suppressor of cytokine signaling (SOCS)-3: " Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1 induced transcription and activation of NFkappaB and the MAPKs JNK and p38 , but the mechanism is unknown "

NFkappaB ⊣ (SOCS)-3: " Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1 induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown "

NFkappaB ⊣ Suppressor of cytokine signaling (SOCS)-3: " Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1 induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown "

p38 → IL-1: " Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1 induced transcription and activation of NFkappaB and the MAPKs JNK and p38 , but the mechanism is unknown "

NFkappaB → IL-1: " Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1 induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown "

TRAF6 ⊣ SOCS-3: " By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6 "

TAK1 ⊣ SOCS-3: " By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6 "

TAK1 ⊣ SOCS-3: " Furthermore, SOCS-3 inhibited the IL-1 induced catalytic activity of TAK1 "

TAK1 ⊣ SOCS-3: " Furthermore, SOCS-3 inhibited the IL-1 induced catalytic activity of TAK1 "

TAK1 → IL-1: " Furthermore, SOCS-3 inhibited the IL-1 induced catalytic activity of TAK1 "

TRAF6 ⊣ SOCS-3: " Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS-3 inhibited ubiquitin modification of TRAF6 "

Manually curated Databases

  • IRef Biogrid Interaction: SOCS3 — MAP3K7 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SOCS3 — TRAF6 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TRAF6 — MAP3K7 (physical association, affinity chromatography technology)
  • MIPS CORUM TRAF6-TAK1 complex: TRAF6-TAK1 complex complex (MAP3K7-TRAF6)
  • IRef Corum Interaction: MAP3K7 — TRAF6 (association, coimmunoprecipitation)
In total, 3 gene pairs are associated to this article in curated databases