The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart
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-media...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/11/4/654 |
| _version_ | 1797481823525142528 |
|---|---|
| author | Joshua Abd Alla Ursula Quitterer |
| author_facet | Joshua Abd Alla Ursula Quitterer |
| author_sort | Joshua Abd Alla |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T22:21:01Z |
| format | Article |
| id | doaj.art-46322e8c391a41fcbbc906f4f9f798ea |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T22:21:01Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-46322e8c391a41fcbbc906f4f9f798ea2023-11-23T19:14:49ZengMDPI AGCells2073-44092022-02-0111465410.3390/cells11040654The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the HeartJoshua Abd Alla0Ursula Quitterer1Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, SwitzerlandMolecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, SwitzerlandThe 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.https://www.mdpi.com/2073-4409/11/4/654RKIP (RAF kinase inhibitor protein)<i>PEBP1</i> (phosphatidylethanolamine-binding protein 1)<i>RAF1</i><i>GRK2</i> (G protein-coupled receptor kinase 2)<i>AGTR1</i> (angiotensin II receptor type 1)<i>MAPK</i> (mitogen-activated protein kinase) |
| spellingShingle | Joshua Abd Alla Ursula Quitterer The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart Cells RKIP (RAF kinase inhibitor protein) <i>PEBP1</i> (phosphatidylethanolamine-binding protein 1) <i>RAF1</i> <i>GRK2</i> (G protein-coupled receptor kinase 2) <i>AGTR1</i> (angiotensin II receptor type 1) <i>MAPK</i> (mitogen-activated protein kinase) |
| title | The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart |
| title_full | The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart |
| title_fullStr | The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart |
| title_full_unstemmed | The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart |
| title_short | The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart |
| title_sort | raf kinase inhibitor protein rkip good as tumour suppressor bad for the heart |
| topic | RKIP (RAF kinase inhibitor protein) <i>PEBP1</i> (phosphatidylethanolamine-binding protein 1) <i>RAF1</i> <i>GRK2</i> (G protein-coupled receptor kinase 2) <i>AGTR1</i> (angiotensin II receptor type 1) <i>MAPK</i> (mitogen-activated protein kinase) |
| url | https://www.mdpi.com/2073-4409/11/4/654 |
| work_keys_str_mv | AT joshuaabdalla therafkinaseinhibitorproteinrkipgoodastumoursuppressorbadfortheheart AT ursulaquitterer therafkinaseinhibitorproteinrkipgoodastumoursuppressorbadfortheheart AT joshuaabdalla rafkinaseinhibitorproteinrkipgoodastumoursuppressorbadfortheheart AT ursulaquitterer rafkinaseinhibitorproteinrkipgoodastumoursuppressorbadfortheheart |