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