Abstract
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.
Highlights
The phosphatidylethanolamine-binding protein 1 (PEBP1) inhibits tumour metastasis initiation and acts as an endogenous tumour suppressor [1,2]
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-mitogen-activated protein kinase (MAPK) pathway inhibition
This review aims to delineate how the multifunctional protein and GRK2 inhibitor RKIP accounts for a heart failure phenotype despite cardioprotective signalling stimulated by GRK2 inhibition
Summary
The phosphatidylethanolamine-binding protein 1 (PEBP1) inhibits tumour metastasis initiation and acts as an endogenous tumour suppressor [1,2]. The underlying reason is the fact that all currently approved inhibitors of the RAF-MEK-ERK pathway have cardiotoxic side effects due to their apoptosis-enhancing activities and inhibition of the pro-survival RAF-MAPK pathway signalling [7,8,9]. Several studies showed that potential cardioprotective activities of RKIP were counteracted in vivo by RKIP-mediated inhibition of the pro-survival RAF1-MAPK pathway and/or GRK2 inhibition-induced sensitisation of heart failure-promoting GPCRs such as the angiotensin II receptor type 1 (AGTR1), which impairs cardiac function [21,22,23]. The PEBP1 alias RKIP acts as a RAF kinase inhibitor protein, which is regulated by PKC phosphorylation
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