ArticleThe EMBO journal2014
Ubiquitin-dependent regulation of MEKK2/3-MEK5-ERK5 signaling module by XIAP and cIAP1.
Article in The EMBO journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Targeting ubiquitination in disease and therapy.Signal transduction and targeted therapy · 2025Review
- Targeting the RBM39-MEK5 axis synergizes with bortezomib to inhibit the malignant growth of multiple myeloma.Blood advances · 2025Article
- The regulation of inhibitor of apoptosis proteins (IAPs) during the apoptosis ofFrontiers in physiology · 2023Article
- XIAP promotes melanoma growth by inducing tumour neutrophil infiltration.EMBO reports · 2022Article
- Subcellular localization of X-linked inhibitor of apoptosis protein (XIAP) in cancer: Does that matter?BBA advances · 2022Review
- MicroRNA-211 Modulates the DUSP6-ERK5 Signaling Axis to Promote BRAFThe Journal of investigative dermatology · 2021Article
- Review
- Article
- IL-17R-EGFR axis links wound healing to tumorigenesis in Lrig1The Journal of experimental medicine · 2019Article
- Site-specific polyubiquitination differentially regulates parathyroid hormone receptor-initiated MAPK signaling and cell proliferation.The Journal of biological chemistry · 2018Article
- Ubiquitin-dependent regulation of Cdc42 by XIAP.Cell death & disease · 2017Article
- The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms.eLife · 2017Article
- SIRT1 may play a crucial role in overload-induced hypertrophy of skeletal muscle.The Journal of physiology · 2017Article
- Changes in PUB22 Ubiquitination Modes Triggered by MITOGEN-ACTIVATED PROTEIN KINASE3 Dampen the Immune Response.The Plant cell · 2017Article
- Regulating the balance between necroptosis, apoptosis and inflammation by inhibitors of apoptosis proteins.Immunology and cell biology · 2017Review
- JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships.Microbiology and molecular biology reviews : MMBR · 2016Review
- A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy.Drug discovery today · 2016Review
- Expanding the ubiquitin code through post-translational modification.EMBO reports · 2015Review
- ERK5 signaling gets XIAPed: a role for ubiquitin in the disassembly of a MAPK cascade.The EMBO journal · 2014Article
- Divide and rule: The role of ubiquitination in inactivation of the ERK5-MAPK cascade.Molecular & cellular oncologyArticle
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9 authors at 4 institutions in 2 countries.
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Abstract
Mitogen-activated protein kinases (MAPKs) are highly conserved protein kinase modules, and they control fundamental cellular processes. While the activation of MAPKs has been well studied, little is known on the mechanisms driving their inactivation. Here we uncover a role for ubiquitination in the inactivation of a MAPK module. Extracellular-signal-regulated kinase 5 (ERK5) is a unique, conserved member of the MAPK family and is activated in response to various stimuli through a three-tier cascade constituting MEK5 and MEKK2/3. We reveal an unexpected role for Inhibitors of Apoptosis Proteins (IAPs) in the inactivation of ERK5 pathway in a bimodal manner involving direct interaction and ubiquitination. XIAP directly interacts with MEKK2/3 and competes with PB1 domain-mediated binding to MEK5. XIAP and cIAP1 conjugate predominantly K63-linked ubiquitin chains to MEKK2 and MEKK3 which directly impede MEK5-ERK5 interaction in a trimeric complex leading to ERK5 inactivation. Consistently, loss of XIAP or cIAP1 by various strategies leads to hyperactivation of ERK5 in normal and tumorigenic cells. Loss of XIAP promotes differentiation of human primary skeletal myoblasts to myocytes in a MEKK2/3-ERK5-dependent manner. Our results reveal a novel, obligatory role for IAPs and ubiquitination in the physical and functional disassembly of ERK5-MAPK module and human muscle cell differentiation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.