Targeting Raf Kinase Inhibitory Protein Regulation and Function

Abstract

Raf Kinase Inhibitory Protein (RKIP) is a highly conserved kinase inhibitor that functions as a metastasis suppressor in a variety of cancers. Since RKIP can reprogram tumor cells to a non-metastatic state by rewiring kinase networks, elucidating the mechanism by which RKIP acts not only reveals molecular mechanisms that regulate metastasis, but also represents an opportunity to target these signaling networks therapeutically. Although RKIP is often lost during metastatic progression, the mechanism by which this occurs in tumor cells is complex and not well understood. In this review, we summarize our current understanding of RKIP regulation in tumors and consider experimental and computational strategies for recovering or mimicking its function by targeting mediators of metastasis.

Keywords: RKIP; kinase; metastasis; signaling; suppressor; therapy.

Figure 1

Raf kinase inhibitory protein (RKIP) downregulation in cancers cannot be explained by genetic deletions or mutations as it is rarely deleted or mutated in patient samples (A) Frequency of genetic alterations (mutations, fusions, amplifications, and deep deletions) in PEBP1 (RKIP) genes across multiple TCGA cancer types. (B) Residues on PEBP1 that have been found to be mutated in multiple TCGA cancers. Mutation and sequencing data were accessed through the cBioPortal data base (www.cbioportal.org) [17]. The graphs and figures were generated also on cBioPortal.

Figure 2

Spearman correlations between PEBP1 (RKIP), BACH1 (BTB domain and CNC homolog 1) and the EMT genes CDH1 (E-cadherin), SNAI1 (Snail), SNAI2 (Slug), ZEB1 (Zinc Finger E-Box Binding Homeobox 1), ZEB2 (Zinc Finger E-Box Binding Homeobox 2), TWIST1 (Twist Family BHLH Transcription Factor 1), TWIST2 (Twist Family BHLH Transcription Factor 2), and VIM (vimentin) gene expression in TCGA breast cancer cohort. Correlations are based on RNA-seq data, accessed through cBioPortal database.