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

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.

BBLN triggers CAMK2D pathology in mice under cardiac pressure overload and potentially in unrepaired hearts with tetralogy of Fallot

“…5a ). Concomitantly, transcripts detecting fibrotic cardiac remodeling 32 were increased, for example, Col1a2 , Col3a1 and the collagen-cross-linking enzyme, lysyl oxidase-like 2, Loxl2 (Fig. 5b ).…”

“…f and g ). e – g , Immunohistological determination of BBLN on cardiac specimens of 16 acyanotic TOF patients 1 – 16 and 16 cyanotic TOF patients 17 – 32 . Counterstaining was performed with hematoxylin (HE).…”

“…Besides surgery, specific treatment options for TOF patients are not available, mostly g). e-g, Immunohistological determination of BBLN on cardiac specimens of 16 acyanotic TOF patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and 16 cyanotic TOF patients [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . Counterstaining was performed with hematoxylin (HE).…”