Signaling crossroads: the function of Raf kinase inhibitory protein in cancer, the central nervous system and reproduction. Cell Signalling

Department of Molecular Biology Cell Biology and Biochemistry, Brown University, Providence, RI 02912, United States.
Cellular Signalling (Impact Factor: 4.32). 02/2008; 20(1):1-9. DOI: 10.1016/j.cellsig.2007.07.003
Source: PubMed


The Raf kinase inhibitory protein 1 (RKIP-1) and its orthologs are conserved throughout evolution and widely expressed in eukaryotic organisms. In its non-phosphorylated form RKIP-1 negatively regulates the Raf/MEK/ERK pathway by interfering with the activity of Raf-1. In its phosphorylated state, RKIP-1 dissociates from Raf-1 and inhibits GRK-2, a negative regulator of G-protein coupled receptors (GPCRs). Available data indicate that the phosphorylation of RKIP-1 by PKC can stimulate both the Raf/MEK/ERK and GPCR pathways. RKIP-1 has also been implicated as a negative regulator of the NF-kappaB pathway. Recent studies have shown that phosphorylated RKIP-1 binds to the centrosomal and kinetochore regions of metaphase chromosomes, where it may be involved in regulating the partitioning of chromosomes and the progression through mitosis. The collective evidence indicates that RKIP-1 regulates the activity and mediates the crosstalk between several important cellular signaling pathways. A variety of ablative interventions suggest that reduced RKIP-1 function may influence metastasis, angiogenesis, resistance to apoptosis, and genome integrity. Attenuation of RKIP-1 may also affect cardiac and neurological functions, spermatogenesis, sperm decapacitation, and reproductive behavior. In this review, the role of RKIP-1 in cellular signaling, and especially its functions revealed using a mouse knockout model, are discussed.

Download full-text


Available from: Steven Theroux
  • Source
    • "Raf1 kinase inhibitor protein (RKIP) regulates multiple important signal pathways including Raf1/MEK/ ERK, Nuclear Factor jB and G-protein coupled receptors (Klysik et al. 2008). These signal pathways are closely related to cell differentiation, proliferation, and death (Lorenz et al. 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Raf1 kinase inhibitor protein (RKIP) negatively regulates the Raf1/MEK/ERK pathway which is vital for cell growth and differentiation. It is also a biomarker in clinical cancer diagnosis. RKIP binds to the N-terminus of Raf1 kinase but little is known about the structural basis of RKIP binding with Raf1. Here, we demonstrate that the N-terminus of human Raf1 kinase (hRaf11-147aa) binds with human RKIP (hRKIP) at its ligand-binding pocket, loop "127-149", and the C-terminal helix by NMR experiments. D70, D72, E83, Y120, and Y181 were further verified as the key residues participating in the interaction of hRKIP and hRaf11-147aa. G143-R146 fragment was also critical for hRKIP binding with hRaf11-147aa, for its deletion decreased the binding affinity around 300 times, from 154 to 0.46 mM(-1). Our results provide important structural clues for designing the lead compound that disrupts RKIP-Raf1 interaction.
    Full-text · Article · May 2014 · Biotechnology Letters
  • Source
    • "Furthermore, a combination of Raf and mTOR inhibitors reduces glioma cell proliferation and invasion [5]. Raf kinase inhibitory protein (RKIP), also known as phosphatidylethanolamine binding protein, is involved in regulation of growth and differentiation of mammalian cells by inhibiting Raf and thereby negatively regulating growth factor signaling by the Ras/Raf/MAPK signal transduction pathway [6–8]. Lack of RKIP has been shown to promote tumor progression in a variety of human cancers [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor in cancer cells. MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on antimetastasis strategy. In this study, we found that the expression of RKIP and miR-98 in glioma tissues were significantly lower than that in normal brain tissues. Overexpression of RKIP upregulated miR-98 expression and inhibited glioma cell invasion and miR-98 target gene HMGA2 but had no effect in glioma cell proliferation. Moreover, forced expression of miR-98 accelerated the inhibition of glioma cell invasion and the expression of HMGA2 also had no effect in glioma cell proliferation. Our findings newly described RKIP/miR-98 to HMGA2 link and provided a potential mechanism for glioma cell invasion. RKIP and miR-98 may illustrate the potential therapeutic utility of signaling pathway signatures.
    Full-text · Article · Dec 2013
  • Source
    • "Various isoforms of PKC have been shown to phosphorylate RKIP on S153 which results in the disassociation of Raf-1 and RKIP. For this reason, we thought that missing of RKIP in its nonphosphorylated form in some PC patients may be due to its conversion to the phosphorylated state by PKC which subsequently stimulate both the Raf/MEK/ERK and of Gprotein coupled receptors pathways [14] [15]. Since the loss of RKIP was concomitant with increased expression of PSA, PSMA, and Raf-1/MEK/ERK signaling pathway, we suggested a cross-talk between RKIP/Raf-1/MEK/ERK cascade, PSA and PSMA expression in PC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: To investigate differences in the biological features of the most immunoexpressed prostate cancer (PC) profiles (PSA+, PSMA+) according to the RKIP. Methods: 19 PC with dominant Gleason grade ≥ 8 were studied. Expression of PSA, PSMA, RKIP, Raf-1, MEK-1, ERK-1, ERK-2, p-Akt (T308), p-Akt (S473), NF- κ B p50, and NF- κ Bp65 were detected immunohistochemically. Results: . Loss of RKIP in the most immunoexpressed PC (PSA+, PSMA+) profile was associated with increased levels of PSA and PSMA expression. Intensities of immunoreactions to PSA and PSMA were higher in cancer cells negative for RKIP (12.51 ± 1.6 and 34.95 ± 1.92) compared to those positive for RKIP (4.68 ± 1.11 and 28.56 ± 0.91). In parallel, missing RKIP expression in PC patients with PSA+, PSMA+ profile was connected with increased components of both Raf-1/MEK/ERK and NF- κ B (p65/p50), whereas Akt is activated independently of RKIP. Conclusions: Although characterized by the same (PSA+, PSMA+) profile, PC phenotype missing the RKIP related to invasive potential and greater biological aggressiveness reflected in overexpression of components of Raf-1/MEK/ERK and NF- κ B (p65/p50) in which Akt is activated independently of RKIP. Taking into account the PC phenotypes according to RKIP among PSA-PSMA profiles may improve distinguishing them from cancers that will become more aggressive and therefore adapt the therapeutic strategies in those patients.
    Full-text · Article · Aug 2013
Show more