Elsevier

Cellular Signalling

Volume 20, Issue 1, January 2008, Pages 1-9
Cellular Signalling

Review
Signaling crossroads: The function of Raf kinase inhibitory protein in cancer, the central nervous system and reproduction

https://doi.org/10.1016/j.cellsig.2007.07.003Get rights and content

Abstract

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-κB 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.

Introduction

The history of Raf Kinase Inhibitory Protein (RKIP-1) is more than two decades long and goes back to the work of Bernier et al. [1] who, having isolated the protein based on its ability to bind phospholipids, coined it's original name: phosphatidylethanolamine-binding protein (PEBP). Later, it was found that RKIP-1 is a widely expressed and highly conserved protein that does not share significant homology with any known protein family. In recent years, there has been an increased interest in RKIP-1 due to the discovery of its ability to influence intracellular signaling cascades, cell cycle regulation, the suppression of metastasis, neurodegenerative processes, the modulation of emotions, and reproduction. This minireview addresses selected aspects of RKIP-1 biology, and in particular its role in intracellular signaling, neurological function and reproduction. Excellent reviews have been published recently on other RKIP-1 functions [2], [3], [4], [5].

Section snippets

The RKIP-1 gene and protein

The RKIP gene family is evolutionarily conserved, and its members can be found across distant species [6]. In humans, in addition to RKIP-1, there is one other actively transcribed family member, hPEBP4 [7]. In the mouse, there are three known active RKIP genes: RKIP-1 which is ubiquitously expressed, RKIP-2, whose expression is limited to testes [8], [9], and mRKIP-4, a homolog of hPEBP4 located on mouse chromosome 19, whose expression is limited to retinal ganglion cells of the eye [10]. The

RKIP-1 in signaling

It is now well established that RKIP-1 is a member of a large, evolutionarily conserved group of proteins involved in MAP kinase (MAPK) signal transduction. This signaling machinery evolved to rapidly activate nuclear transcription factors in response to extracellular stimuli [5], [27], [28], [29], and it can influence diverse cellular functions including cell proliferation, differentiation and apoptosis. MAP kinase pathways are a three component kinase module comprised of a MAP kinase kinase

RKIP-1 in cancer

Signaling proteins, including those from the MAP kinase superfamily, are often linked to disease states such as cancer [42]. In recent years, RKIP-1 has been identified as a member of a novel class of molecules that suppress the metastatic spread of tumors.

Molecular pathways involved in the detachment, migration of malignant cells from the primary tumor site, and invasive colonization of distant organs are poorly understood. Factors contributing to this process can be classified as those that

RKIP-1 in Alzheimer disease

RKIP-1 has been implicated as a factor in Alzheimer's disease (AD), the most common form of dementia [72], [73]. AD manifests clinically through a progressive decline in multiple cognitive functions. These include memory impairment, aphasia, apraxia, agnosia and/or the loss of ability to plan and organize routine activities. There appear to be two basic forms of AD: early-onset, which affects individuals younger than 65 years of age, and late onset, which takes its toll on individuals older

RKIP-1 and spermatogenesis

The role of RKIP-1 in reproduction is an intriguing and yet to be thoroughly addressed question. In rodents, RKIP-1 and its isoform RKIP-2, are expressed at high levels in the seminiferous tubules, and elongated spermatids [8], [93], [94]. Spermatozoa are highly differentiated cells that require complex and extensive cellular remodeling during spermatogenesis. The acquisition of well-defined protein surface domains begins early during spermiogenesis [95]. Spermiogenetic restructuring takes

RKIP-1 in sperm capacitation

An intriguing hypothesis put forth by Gibbons et al. [103] has implicated RKIP-1 in sperm capacitation. Mammalian sperm cells released from the male reproductive tract are non-fertilizing and must complete maturation before they gain the ability to fertilize an oocyte. This process is termed capacitation, and it involves a loss of proteins from the sperm surface. In vitro, capacitation can be accomplished simply by incubating sperm cells over a period of time. The process is reversible, and if

Conclusions

The Raf kinase inhibitory protein has been studied for more than two decades. Given its multifaceted roles within the cell (Fig. 4) and its ability to suppress metastasis, it is not surprising that RKIP-1 has captured the attention of many laboratories over the last several years. Future studies are under way and the genetic, cellular and molecular properties of RKIP-1 should lead to a more complete understanding of its function. The recently established mouse model should play an important

Acknowledgements

This work was supported by grants 5P42ES013660-02 and 5P20RR015578-07 from the National Institute of Health.

References (104)

  • I. Bernier et al.

    Biochim. Biophys. Acta

    (1986)
  • E.T. Keller et al.

    Biochem. Pharmacol.

    (2004)
  • G. Odabaei et al.

    Adv. Cancer Res.

    (2004)
  • X. Wang et al.

    J. Biol. Chem.

    (2004)
  • S. Theroux et al.

    Brain Res. Bull.

    (2007)
  • G. Rautureau et al.

    Protein Expr. Purif.

    (2006)
  • D. Gems et al.

    J. Biol. Chem.

    (1995)
  • K.D. Erttmann et al.

    Gene

    (1996)
  • F. Trottein et al.

    Mol. Biochem. Parasitol.

    (1995)
  • U. Hengst et al.

    J. Biol. Chem.

    (2001)
  • K. Ojika et al.

    Prog. Neurobiol.

    (2000)
  • K. Ojika et al.

    Brain Res.

    (1995)
  • N. Tohdoh et al.

    Brain Res. Mol. Brain Res.

    (1995)
  • Y. Goumon et al.

    J. Biol. Chem.

    (2004)
  • M.J. Banfield et al.

    Structure

    (1998)
  • L. Serre et al.

    J. Mol. Biol.

    (2001)
  • L. Serre et al.

    Structure

    (1998)
  • D.K. Morrison et al.

    J. Biol. Chem.

    (1993)
  • E.M. Eves et al.

    Mol. Cell

    (2006)
  • T. Kroslak et al.

    J. Biol. Chem.

    (2001)
  • K.C. Corbit et al.

    J. Biol. Chem.

    (2003)
  • G.P. Gupta et al.

    Cell

    (2006)
  • J.R. Graff et al.

    J. Biol. Chem.

    (2000)
  • A. West et al.

    Genomics

    (1998)
  • J. Tapper et al.

    Cancer Genet. Cytogenet.

    (2001)
  • D. Chatterjee et al.

    J. Biol. Chem.

    (2004)
  • L. Zhang et al.

    Surgery

    (2004)
  • H.C. Lee et al.

    Gastroenterology

    (2006)
  • G. Helbig et al.

    J. Biol. Chem.

    (2003)
  • S. Zhu et al.

    Chem. Biol.

    (2005)
  • J. Hardy

    Trends Neurosci.

    (1997)
  • R.E. Tanzi et al.

    Neuron

    (2001)
  • K. Ojika et al.

    Brain Res. Dev. Brain Res.

    (1994)
  • A.J. George et al.

    Neurobiol. Aging

    (2006)
  • C. Dulac et al.

    Cell

    (1995)
  • N.J. Ryba et al.

    Neuron

    (1997)
  • H. Matsunami et al.

    Cell

    (1997)
  • P.T.K. Saunders et al.

    Molec. Cell. Endocrinol.

    (1995)
  • M. Nikolopoulou et al.

    Biochim. Biophys. Acta

    (1985)
  • R. Jones et al.

    Dev. Biol.

    (1990)
  • R. Jones et al.

    Biochem. J.

    (1987)
  • E.T. Keller et al.

    J. Cell. Biochem.

    (2005)
  • N. Trakul et al.

    Cell. Res.

    (2005)
  • J. Frayne et al.

    Cell Tissue Res.

    (1999)
  • D.M. Hickox et al.

    Biol. Reprod.

    (2002)
  • Y. Zhang et al.

    J. Wang. Int. J. Mol. Med.

    (2007)
  • D. Bradley et al.

    Nature

    (1996)
  • S. Ohshima et al.

    Mol. Gen. Genet.

    (1997)
  • L. Pnueli et al.

    Plant Cell

    (2001)
  • T. Angelone et al.

    J. Pharmacol. Exp. Ther.

    (2006)
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      Citation Excerpt :

      Raf kinase inhibitor protein (RKIP), a member of the phosphatidylethanolamine-binding protein (PEBP) families, is a physiologically relevant inhibitor of Raf-MEK-ERK (Escara-Wilke et al., 2012; Keller et al., 2004). RKIP is reported to be involved in metastasis, angiogenesis, cell apoptosis, genome integrity and EndMT, thus influencing many biological progresses, including cancer, cardiac and neurological functions, spermatogenesis, sperm decapacitation, and reproductive behavior (Baritaki et al., 2010; Klysik et al., 2008). In our previous study, we found that the protein level of RKIP was significantly decreased in vitreous humor of PDR patients (Wang et al., 2012, 2013), which indicated us that RKIP might play a role in the development of PDR.

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