TY - JOUR
T1 - Regulation of the MAPK pathway by Raf kinase inhibitory protein
AU - Vandamme, Drieke
AU - Herrero, Ana
AU - Al-Mulla, Fahd
AU - Kolch, Walter
PY - 2014/1/1
Y1 - 2014/1/1
N2 - The Raf kinase inhibitor protein 1 (RKIP-1) was the first reported endogenous inhibitor of Raf-1-MEK-ERK/MAPK cascade, by interfering with the phosphorylation of MEK by Raf-1. However, RKIP’s functions related to the MAPK signaling are far more complex. Newer data indicate that by modulating different protein-protein interactions, RKIP is involved in fine-tuning cell signaling, modulating ERK dynamics, and regulating cross talk between different pathways. Here, we describe the molecular mechanisms by which RKIP controls MAPK signaling at different levels and vice versa and its regulation via feedback phosphorylation. We also focus on several discrepancies and questions that remain, such as the RKIP binding regulation by Raf-1 N-region phosphorylation, the possible B-Raf inhibition, and the effects of RKIP-lipid binding. We also describe how RKIP’s role as key signaling modulator of many cell fate decisions leads to the fact that fine control of RKIP activity and regulation is crucial to avoid pathological processes, such as metastasis, pulmonary arterial hypertension, and heart failure.
AB - The Raf kinase inhibitor protein 1 (RKIP-1) was the first reported endogenous inhibitor of Raf-1-MEK-ERK/MAPK cascade, by interfering with the phosphorylation of MEK by Raf-1. However, RKIP’s functions related to the MAPK signaling are far more complex. Newer data indicate that by modulating different protein-protein interactions, RKIP is involved in fine-tuning cell signaling, modulating ERK dynamics, and regulating cross talk between different pathways. Here, we describe the molecular mechanisms by which RKIP controls MAPK signaling at different levels and vice versa and its regulation via feedback phosphorylation. We also focus on several discrepancies and questions that remain, such as the RKIP binding regulation by Raf-1 N-region phosphorylation, the possible B-Raf inhibition, and the effects of RKIP-lipid binding. We also describe how RKIP’s role as key signaling modulator of many cell fate decisions leads to the fact that fine control of RKIP activity and regulation is crucial to avoid pathological processes, such as metastasis, pulmonary arterial hypertension, and heart failure.
KW - Lipid binding
KW - MAPK signaling
KW - Pathology
KW - Raf
KW - RKIP
UR - http://www.scopus.com/inward/record.url?scp=84911992888&partnerID=8YFLogxK
U2 - 10.1615/CritRevOncog.2014011922
DO - 10.1615/CritRevOncog.2014011922
M3 - Article
C2 - 25597351
AN - SCOPUS:84911992888
VL - 19
SP - 405
EP - 415
JO - Critical Reviews in Oncogenesis
JF - Critical Reviews in Oncogenesis
SN - 0893-9675
IS - 6
ER -