ArticleThe Journal of biological chemistry2012
Raf kinase inhibitor protein (RKIP) dimer formation controls its target switch from Raf1 to G protein-coupled receptor kinase (GRK) 2.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 67 citations in OpenAlex.
- Review
- Two Cysteines in Raf Kinase Inhibitor Protein Make Differential Contributions to Structural Dynamics In Vitro.Molecules (Basel, Switzerland) · 2025Article
- Unraveling the RKIP-YY1 axis: immune crosstalk in the pathogenesis of metabolic disorders.Frontiers in immunology · 2025Review
- Emerging modes of regulation of neuromodulatory G protein-coupled receptors.Trends in neurosciences · 2024Review
- Review
- Membrane regulation of 15LOX-1/PEBP1 complex prompts the generation of ferroptotic signals, oxygenated PEs.Free radical biology & medicine · 2023Article
- Cancer resistance via the downregulation of the tumor suppressorsExploration of targeted anti-tumor therapy · 2023Review
- Raf kinase inhibitory protein reduces bradykinin receptor desensitization.Journal of neurochemistry · 2022Article
- Harnessing RKIP to Combat Heart Disease and Cancer.Cancers · 2022Review
- Review
- Review
- Post-translational Modifications of Opioid Receptors.Trends in neurosciences · 2020Review
- Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects.Nature communications · 2020Article
- G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub.Cellular and molecular life sciences : CMLS · 2019Review
- G Protein-Coupled Receptor Kinase 2 (GRK2) as a Potential Therapeutic Target in Cardiovascular and Metabolic Diseases.Frontiers in pharmacology · 2019Review
- The role of G protein-coupled receptor kinases in the pathology of malignant tumors.Acta pharmacologica Sinica · 2018Review
- Exploring Morphine-Triggered PKC-Targets and Their Interaction with Signaling Pathways Leading to Pain via TrkA.Proteomes · 2018Review
- RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact.Cancers · 2018Review
- Sympathetic Nerve Hyperactivity in the Spleen: Causal for Nonpathogenic-Driven Chronic Immune-Mediated Inflammatory Diseases (IMIDs)?International journal of molecular sciences · 2018Review
- Metastasis suppressors: functional pathways.Laboratory investigation; a journal of technical methods and pathology · 2018Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteins controlling cellular networks have evolved distinct mechanisms to ensure specificity in protein-protein interactions. Raf kinase inhibitor protein (RKIP) is a multifaceted kinase modulator, but it is not well understood how this small protein (21 kDa) can coordinate its diverse signaling functions. Raf1 and G protein-coupled receptor kinase (GRK) 2 are direct interaction partners of RKIP and thus provide the possibility to untangle the mechanism of its target specificity. Here, we identify RKIP dimer formation as an important mechanistic feature in the target switch from Raf1 to GRK2. Co-immunoprecipitation and cross-linking experiments revealed RKIP dimerization upon phosphorylation of RKIP at serine 153 utilizing purified proteins as well as in cells overexpressing RKIP. A functional phosphomimetic RKIP mutant had a high propensity for dimerization and reproduced the switch from Raf1 to GRK2. RKIP dimerization and GRK2 binding, but not Raf1 interaction, were prevented by a peptide comprising amino acids 127-146 of RKIP, which suggests that this region is critical for dimer formation. Furthermore, a dimeric RKIP mutant displayed a higher affinity to GRK2, but a lower affinity to Raf1. Functional analyses of phosphomimetic as well as dimeric RKIP demonstrated that enhanced dimerization of RKIP translates into decreased Raf1 and increased GRK2 inhibition. The detection of RKIP dimers in a complex with GRK2 in murine hearts implies their physiological relevance. These findings represent a novel mechanistic feature how RKIP can discriminate between its different interaction partners and thus advances our understanding how specific inhibition of kinases can be achieved.
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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.