ArticleProceedings of the National Academy of Sciences of the United States of America2019
Arrestin-3 scaffolding of the JNK3 cascade suggests a mechanism for signal amplification.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
31 citing papers in PubMed, 45 citations in OpenAlex.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- JNK3 regulates β cell responses to incretins in human islets and mouse models.The Journal of clinical investigation · 2026Article
- HACD3 promotes malignant progression of NSCLC by suppressing the MKK7/MAPK10 signaling axis.BMC cancer · 2025Article
- Helix-bundle and C-terminal GPCR domains differentially influence GRK-specific functions and β-arrestin-mediated regulation.Nature communications · 2025Article
- Development of Mutant MBiochemistry · 2025Article
- Assembling the jigsaw puzzle of life.Trends in biochemical sciences · 2025Article
- Molecular mechanism of β-arrestin-2 pre-activation by phosphatidylinositol 4,5-bisphosphate.EMBO reports · 2024Article
- GPCR-dependent and -independent arrestin signaling.Trends in pharmacological sciences · 2024Review
- Altered microRNA expression profiles of human spermatozoa in normal fertile men of different ages.Asian journal of andrology · 2023Article
- Arrestin-3-Dependent Activation of c-Jun N-Terminal Kinases (JNKs).Current protocols · 2023Article
- Article
- GPCR binding and JNK3 activation by arrestin-3 have different structural requirements.bioRxiv : the preprint server for biology · 2023Article
- G protein-coupled receptor signaling: transducers and effectors.American journal of physiology. Cell physiology · 2022Review
- Short Arrestin-3-Derived Peptides Activate JNK3 in Cells.International journal of molecular sciences · 2022Article
- Scaffolding of Mitogen-Activated Protein Kinase Signaling by β-Arrestins.International journal of molecular sciences · 2022Review
- Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases.Cells · 2020Review
- Many faces of the GPCR-arrestin interaction.Archives of pharmacal research · 2020Review
- Modeling the Control of TGF-β/Smad Nuclear Accumulation by the Hippo Pathway Effectors, Taz/Yap.iScience · 2020Article
- Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Scaffold proteins tether and orient components of a signaling cascade to facilitate signaling. Although much is known about how scaffolds colocalize signaling proteins, it is unclear whether scaffolds promote signal amplification. Here, we used arrestin-3, a scaffold of the ASK1-MKK4/7-JNK3 cascade, as a model to understand signal amplification by a scaffold protein. We found that arrestin-3 exhibited >15-fold higher affinity for inactive JNK3 than for active JNK3, and this change involved a shift in the binding site following JNK3 activation. We used systems biochemistry modeling and Bayesian inference to evaluate how the activation of upstream kinases contributed to JNK3 phosphorylation. Our combined experimental and computational approach suggested that the catalytic phosphorylation rate of JNK3 at Thr-221 by MKK7 is two orders of magnitude faster than the corresponding phosphorylation of Tyr-223 by MKK4 with or without arrestin-3. Finally, we showed that the release of activated JNK3 was critical for signal amplification. Collectively, our data suggest a "conveyor belt" mechanism for signal amplification by scaffold proteins. This mechanism informs on a long-standing mystery for how few upstream kinase molecules activate numerous downstream kinases to amplify signaling.
Indexed as
Identifiers
What OpenQuestion holds
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.