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Both internalization and AIP1 association are required for tumor necrosis factor receptor 2-mediated JNK signaling.
Arterioscler Thromb Vasc Biol. 2012 Sep; 32(9):2271-9.AT

Abstract

OBJECTIVE

The proinflammtory cytokine tumor necrosis factor (TNF), primarily via TNF receptor 1 (TNFR1), induces nuclear factor-κB (NF-κB)-dependent cell survival, and c-Jun N-terminal kinase (JNK) and caspase-dependent cell death, regulating vascular endothelial cell (EC) activation and apoptosis. However, signaling by the second receptor, TNFR2, is poorly understood. The goal of this study was to dissect how TNFR2 mediates NF-κB and JNK signaling in vascular EC, and its relevance to in vivo EC function.

METHODS AND RESULTS

We show that TNFR2 contributes to TNF-induced NF-κB and JNK signaling in EC as TNFR2 deletion or knockdown reduces the TNF responses. To dissect the critical domains of TNFR2 that mediate the TNF responses, we examine the activity of TNFR2 mutant with a specific deletion of the TNFR2 intracellular region, which contains conserved domain I, domain II, domain III, and 2 TNFR-associated factor-2-binding sites. Deletion analyses indicate that different sequences on TNFR2 have distinct roles in NF-κB and JNK activation. Specifically, deletion of the TNFR-associated factor-2-binding sites (TNFR2-59) diminishes the TNFR2-mediated NF-κB, but not JNK activation; whereas, deletion of domain II or domain III blunts TNFR2-mediated JNK but not NF-κB activation. Interestingly, we find that the TNFR-associated factor-2-binding sites ensure TNFR2 on the plasma membrane, but the di-leucine LL motif within the domain II and aa338-355 within the domain III are required for TNFR2 internalization as well as TNFR2-dependent JNK signaling. Moreover, domain III of TNFR2 is responsible for association with ASK1-interacting protein-1, a signaling adaptor critical for TNF-induced JNK signaling. While TNFR2 containing the TNFR-associated factor-2-binding sites prevents EC cell death, a specific activation of JNK without NF-κB activation by TNFR2-59 strongly induces caspase activation and EC apoptosis.

CONCLUSIONS

Our data reveal that both internalization and ASK1-interacting protein-1 association are required for TNFR2-dependent JNK and apoptotic signaling. Controlling TNFR2-mediated JNK and apoptotic signaling in EC may provide a novel strategy for the treatment of vascular diseases.

Authors+Show Affiliations

Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, 10 Amistad St., 401B, New Haven, CT 06520, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22743059

Citation

Ji, Weidong, et al. "Both Internalization and AIP1 Association Are Required for Tumor Necrosis Factor Receptor 2-mediated JNK Signaling." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 9, 2012, pp. 2271-9.
Ji W, Li Y, Wan T, et al. Both internalization and AIP1 association are required for tumor necrosis factor receptor 2-mediated JNK signaling. Arterioscler Thromb Vasc Biol. 2012;32(9):2271-9.
Ji, W., Li, Y., Wan, T., Wang, J., Zhang, H., Chen, H., & Min, W. (2012). Both internalization and AIP1 association are required for tumor necrosis factor receptor 2-mediated JNK signaling. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(9), 2271-9. https://doi.org/10.1161/ATVBAHA.112.253666
Ji W, et al. Both Internalization and AIP1 Association Are Required for Tumor Necrosis Factor Receptor 2-mediated JNK Signaling. Arterioscler Thromb Vasc Biol. 2012;32(9):2271-9. PubMed PMID: 22743059.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Both internalization and AIP1 association are required for tumor necrosis factor receptor 2-mediated JNK signaling. AU - Ji,Weidong, AU - Li,Yonghao, AU - Wan,Ting, AU - Wang,Jing, AU - Zhang,Haifeng, AU - Chen,Hong, AU - Min,Wang, Y1 - 2012/06/28/ PY - 2012/6/30/entrez PY - 2012/6/30/pubmed PY - 2012/10/30/medline SP - 2271 EP - 9 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 32 IS - 9 N2 - OBJECTIVE: The proinflammtory cytokine tumor necrosis factor (TNF), primarily via TNF receptor 1 (TNFR1), induces nuclear factor-κB (NF-κB)-dependent cell survival, and c-Jun N-terminal kinase (JNK) and caspase-dependent cell death, regulating vascular endothelial cell (EC) activation and apoptosis. However, signaling by the second receptor, TNFR2, is poorly understood. The goal of this study was to dissect how TNFR2 mediates NF-κB and JNK signaling in vascular EC, and its relevance to in vivo EC function. METHODS AND RESULTS: We show that TNFR2 contributes to TNF-induced NF-κB and JNK signaling in EC as TNFR2 deletion or knockdown reduces the TNF responses. To dissect the critical domains of TNFR2 that mediate the TNF responses, we examine the activity of TNFR2 mutant with a specific deletion of the TNFR2 intracellular region, which contains conserved domain I, domain II, domain III, and 2 TNFR-associated factor-2-binding sites. Deletion analyses indicate that different sequences on TNFR2 have distinct roles in NF-κB and JNK activation. Specifically, deletion of the TNFR-associated factor-2-binding sites (TNFR2-59) diminishes the TNFR2-mediated NF-κB, but not JNK activation; whereas, deletion of domain II or domain III blunts TNFR2-mediated JNK but not NF-κB activation. Interestingly, we find that the TNFR-associated factor-2-binding sites ensure TNFR2 on the plasma membrane, but the di-leucine LL motif within the domain II and aa338-355 within the domain III are required for TNFR2 internalization as well as TNFR2-dependent JNK signaling. Moreover, domain III of TNFR2 is responsible for association with ASK1-interacting protein-1, a signaling adaptor critical for TNF-induced JNK signaling. While TNFR2 containing the TNFR-associated factor-2-binding sites prevents EC cell death, a specific activation of JNK without NF-κB activation by TNFR2-59 strongly induces caspase activation and EC apoptosis. CONCLUSIONS: Our data reveal that both internalization and ASK1-interacting protein-1 association are required for TNFR2-dependent JNK and apoptotic signaling. Controlling TNFR2-mediated JNK and apoptotic signaling in EC may provide a novel strategy for the treatment of vascular diseases. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/22743059/Both_internalization_and_AIP1_association_are_required_for_tumor_necrosis_factor_receptor_2_mediated_JNK_signaling_ L2 - https://www.ahajournals.org/doi/10.1161/ATVBAHA.112.253666?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -