Phosphatidylenthanolamine Binding Protein aka Raf Kinase Inhibitor Protein: A Brief History of Its Discovery and the Remarkable Diversity of Biological Functions

Abstract

Phosphatidylethanolamine-binding protein (PEBP) was identified almost three decades ago as an abundant protein in bovine brain. PEBP is the prototype of a highly conserved family of proteins represented in all three major phylogenetic divisions, eukaryota, bacteria, and archaea, with no significant sequence homology to other proteins. PEBP proteins have been studied in many species. The most thoroughly explored biological role of PEBP is that of a modulator of intracellular signaling pathways, which is mediated by its ability to bind and inhibit a number of protein kinases. The first such interaction that came to light was with the Raf1 kinase, and PEBP is thus widely referred to in the literature under its alternate name RKIP (Raf kinase inhibitory protein). The activity of RKIP itself is subject to regulation by phosphorylation. Intriguingly, PEBP has also been reported to possess additional, and diverse, biological functions unrelated to protein kinase networks that remain to be investigated in detail. Recent findings that RKIP may function as a suppressor of cancer metastasis are of great interest and importance. Prognostic and therapeutic applications of RKIP in human cancer were the subject of the first international workshop on RKIP that was held at the University of California, Los Angeles, in March 2010. This paper was presented at the workshop as a summary of the history of this still small but rapidly evolving field.

FIGURE 1

Roles of RKIP in intracellular signaling. (A) Downregulation of signaling mediated by inhibitory RKIP actions. (B) Activation of signaling elicited by removal of RKIP. Left: the ERK MAPK pathway. RKIP binds to activated RAF1 and inhibits its interaction with MEK, thus antagonizing MEK phosphorylation and activation. Phosphorylation of RKIP by protein kinase C (PKC) releases RKIP from RAF1. Center: the NF-κB pathway. RKIP interacts with the activating kinases of the NF-κB pathway: transforming growth factor β-activated kinase (TAK), IκB kinase-α (IKK-α), IκB kinase-β (IKK-β), and NF-κB-inducing kinase (NIK). Release of RKIP from TAK, IKKs, and NIK (by an unknown mechanism) results in the phosphorylation and degradation of IκB, which in turn releases NF-κB. Right: G protein–coupled receptor (GPCR) pathways. GPCR kinase-2 (GRK2) antagonizes the activity of GPCRs. Phosphorylation of RKIP by PKC activates it for binding to GRK2, resulting in the inhibition of GRK2 activity. This allows GPCRs to interact with their cognate G-proteins (G), thus promoting GPCR-mediated signaling.