RKIP regulates MAP kinase signaling in cells with defective B-Raf activity

Zeng, Lingchun; Ehrenreiter, Karin; Menon, Jyotsana; Menard, Ray; Kern, Florian; Nakazawa, Yoko; Bevilacqua, Elena; Imamoto, Akira; Baccarini, Manuela; Rosner, Marsha Rich

doi:10.1016/j.cellsig.2013.02.005

Cited by 8 publications

(6 citation statements)

References 28 publications

(46 reference statements)

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“…As the mechanism for p-Erk increase, we observed the RKIP reduction (Figure 2 ). Although RKIP is well known inhibitor of Raf kinase, it can also block the MEK1/2 activation [ 32 ]. In fact, silica-induced p-Erk was not suppressed by MEK1/2 inhibitors (Figure 1E ).…”

Section: Discussionmentioning

confidence: 99%

NF2 blocks Snail-mediated p53 suppression in mesothelioma

Cho

Yoon

et al. 2015

Oncotarget

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Although asbestos causes malignant pleural mesothelioma (MPM), rising from lung mesothelium, the molecular mechanism has not been suggested until now. Extremely low mutation rate in classical tumor suppressor genes (such as p53 and pRb) and oncogenes (including Ras or myc) indicates that there would be MPM-specific carcinogenesis pathway. To address this, we treated silica to mimic mesothelioma carcinogenesis in mesothelioma and non-small cell lung cancer cell lines (NSCLC). Treatment of silica induced p-Erk and Snail through RKIP reduction. In addition, p53 and E-cadherin were decreased by silica-treatment. Elimination of Snail restored p53 expression. We found that NF2 (frequently deleted in MPM) inhibited Snail-mediated p53 suppression and was stabilized by RKIP. Importantly, GN25, an inhibitor of p53-Snail interaction, induced p53 and apoptosis. These results indicate that MPM can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail. Thus, the p53-Snail binding inhibitor such as GN25 is a drug candidate for MPM.

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Section: Discussionmentioning

confidence: 99%

NF2 blocks Snail-mediated p53 suppression in mesothelioma

Cho

Yoon

et al. 2015

Oncotarget

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“…Code S1. A text file with computer-readable model implementation written in BNGL References (49)(50)(51)(52)(53)(54)(55)(56)…”

Section: Computational Modelingmentioning

confidence: 99%

RAF1/BRAF dimerization integrates the signal from RAS to ERK and ROKα

et al. 2017

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Downstream of growth factor receptors and of the guanine triphosphatase (GTPase) RAS, heterodimers of the serine/threonine kinases BRAF and RAF1 are critical upstream kinases and activators of the mitogen-activated protein kinase (MAPK) module containing the mitogen-activated and extracellular signal-regulated kinase kinase (MEK) and their targets, the extracellular signal-regulated kinase (ERK) family. Either direct or scaffold protein-mediated interactions among the components of the ERK module (the MAPKKKs BRAF and RAF1, MEK, and ERK) facilitate signal transmission. RAF1 also has essential functions in the control of tumorigenesis and migration that are mediated through its interaction with the kinase ROKα, an effector of the GTPase RHO and regulator of cytoskeletal rearrangements. We combined mutational and kinetic analysis with mathematical modeling to show that the interaction of RAF1 with ROKα is coordinated with the role of RAF1 in the ERK pathway. We found that the phosphorylated form of RAF1 that interacted with and inhibited ROKα was generated during the interaction of RAF1 with the ERK module. This mechanism adds plasticity to the ERK pathway, enabling signal diversification at the level of both ERK and RAF. Furthermore, by connecting ERK activation with the regulation of ROKα and cytoskeletal rearrangements by RAF1, this mechanism has the potential to precisely coordinate the proper timing of proliferation with changes in cell shape, adhesion, or motility.

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“…Subsequent studies confirmed the function of RKIP as RAF1 inhibitor [ 53 , 54 ]. It was found that RKIP, depending on the cellular background, not only inhibits RAF1 but also BRAF [ 55 , 56 , 57 ].…”

Section: Tumour Suppressor Functions Of Rkipmentioning

confidence: 99%

The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart

Alla

Quitterer

2022

Cells

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The RAF kinase inhibitor protein, RKIP, is a dual inhibitor of the RAF1 kinase and the G protein-coupled receptor kinase 2, GRK2. By inhibition of the RAF1-MAPK (mitogen-activated protein kinase) pathway, RKIP acts as a beneficial tumour suppressor. By inhibition of GRK2, RKIP counteracts GRK2-mediated desensitisation of G protein-coupled receptor (GPCR) signalling. GRK2 inhibition is considered to be cardioprotective under conditions of exaggerated GRK2 activity such as heart failure. However, cardioprotective GRK2 inhibition and pro-survival RAF1-MAPK pathway inhibition counteract each other, because inhibition of the pro-survival RAF1-MAPK cascade is detrimental for the heart. Therefore, the question arises, what is the net effect of these apparently divergent functions of RKIP in vivo? The available data show that, on one hand, GRK2 inhibition promotes cardioprotective signalling in isolated cardiomyocytes. On the other hand, inhibition of the pro-survival RAF1-MAPK pathway by RKIP deteriorates cardiomyocyte viability. In agreement with cardiotoxic effects, endogenous RKIP promotes cardiac fibrosis under conditions of cardiac stress, and transgenic RKIP induces heart dysfunction. Supported by next-generation sequencing (NGS) data of the RKIP-induced cardiac transcriptome, this review provides an overview of different RKIP functions and explains how beneficial GRK2 inhibition can go awry by RAF1-MAPK pathway inhibition. Based on RKIP studies, requirements for the development of a cardioprotective GRK2 inhibitor are deduced.

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RKIP regulates MAP kinase signaling in cells with defective B-Raf activity

Cited by 8 publications

References 28 publications

NF2 blocks Snail-mediated p53 suppression in mesothelioma

NF2 blocks Snail-mediated p53 suppression in mesothelioma

RAF1/BRAF dimerization integrates the signal from RAS to ERK and ROKα

The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart

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