Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada
* Author for correspondence (e-mail: quarmby{at}sfu.ca)
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Summary |
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Key words: Flagella, Cell cycle, NIMA, Kinase, Basal body
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Introduction |
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There are eleven orthologous Nek genes in mice and humans (Table 1) (Caenepeel et al., 2004; Forrest et al., 2003
). A phylogenetic analysis of 81 Nek sequences from a wide variety of eukaryotes and four kinases from outside the family produces a phylogenetic tree in which most branches are poorly resolved (not shown). Of these, the three well-resolved clades are shown in Fig. 1. Note this analysis does not include the 39 Neks recently found in the genome of the ciliate Tetrahymena thermophila (J. Gaertig, personal communication). This large expansion of the Nek family may reflect the numerous and specialized cilia found on this sophisticated unicellular organism, since several of these proteins appear to regulate cilium length (J. Gaertig, personal communication). Nevertheless, lineage-specific expansions, such as those seen in the higher plants and Tetrahymena, are less likely to be informative with respect to ancestral functions. Thus, in this Commentary we focus on the members of the family that are more likely to provide such clues.
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Below, we review what is known about the Nek proteins mainly in the context of clades because, despite the potential for substantial evolution of function, we wish to explore the possibility that proteins within a clade might share ancestral protein-protein interactions and conserved cellular functions. We focus on the best-characterized members of the family rather than provide a comprehensive catalog of initial characterizations. We then examine the hypothesis that the Nek family coevolved with centrioles that serve dual functions as basal bodies and foci for mitotic spindles.
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The Nek2/NIMA clade: G2-M regulation and centrosome separation |
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Do these activities reflect those of Neks in other organisms? TINC appears to be a protein specific to filamentous fungi. This mechanism of nuclear membrane fission might therefore be specific to this group (Davies et al., 2004). However, a role for NIMA in nuclear membrane fission might be common to all fungi: the kinase activity of the Schizosaccharomyces pombe NIMA ortholog (Fin1p) peaks at the metaphase-anaphase transition, and fin1-deletion mutants have extensive elaborations of the nuclear envelope (Krien et al., 2002
). Roles in nuclear envelope fission could represent neo-functionalization of the ancestral Nek within the fungi. By contrast, the role of NIMA in mitotic entry might provide more clues to essential early activities. Ectopic expression of the Aspergillus NIMA in mammalian cells triggers partial disassembly of the NPC, nuclear envelope breakdown and DNA condensation (Lu and Hunter, 1995a
). A mammalian Nek might thus play a role in NPC disassembly (De Souza et al., 2004
) and, as the closest relative of NIMA, Nek2 would be the most likely candidate.
Vertebrate Nek2 is an important player in the coordination of centrosome structure and function with mitotic progression, and localizes mainly to centrosomes throughout the cell cycle (Fry et al., 1998b). Most of the Nek2 protein at the centrosome is rapidly turned over (t
3 seconds), and multiple processes regulate its centrosomal abundance (Hames et al., 2005
). Nek2 is dimeric and is activated by autophosphorylation (Fry et al., 1999
; Fry et al., 1995
). There are two splice variants of vertebrate Nek2: Nek2A has an N-terminal kinase domain, a C-terminal domain that includes a leucine zipper, a protein phosphatase 1c (PP1c)-binding domain, and a motif that targets it for destruction by the anaphase-promoting complex [APC/C (Fry et al., 1999
; Hames et al., 2005
)]; Nek2B, lacks the PP1c-binding domain and the destruction box (Hames et al., 2005
). Nek2A is more abundant in adult cells; by contrast, only Nek2B is detected in Xenopus eggs and early embryos (Fry et al., 2000
). Nek2B is rapidly recruited to sperm basal bodies in the zygotic centrosome and is essential for assembly and maintenance of centrosomes in the early embryo (Fry et al., 2000
; Twomey et al., 2004
; Uto and Sagata, 2000
).
Nek2A is required for centrosome separation (disjunction) at the G2-M cell-cycle transition (Fry, 2002). Among the centrosomal targets of Nek2 kinase activity are C-Nap1, a core centrosomal protein that helps keep the centrioles together throughout interphase (Fry et al., 1998a
; Mayor et al., 2002
; Mayor et al., 2000
), and ninein-like protein [Nlp (Rapley et al., 2005
)]. C-Nap1 and Nlp are displaced from the centrosome at G2-M and phosphorylation of these proteins by Nek2 contributes to this displacement (Fry et al., 1998a
; Mayor et al., 2002
; Rapley et al., 2005
). Although the roles of C-Nap1 and Nlp in centrosome disjunction remain enigmatic, it is clear that Nek2 plays an important role in the process. Transient overexpression of Nek2 causes a splitting of centrosomes (Fry et al., 1998b
), whereas expression of a kinase-dead Nek2A blocks normal centrosome disjunction and, consequently, bipolar spindle formation (Faragher and Fry, 2003
). Thus, Nek2A kinase activity is essential for this key mitotic event.
Polo-like kinase 1 (Plk1) is another centrosomal kinase that becomes localized to the centrosome and is active at G2-M (Golsteyn et al., 1995). Recognition of certain substrates by Plk1 is enhanced by prior phosphorylation of the substrates by another kinase (Elia et al., 2003
). Studies by Rapley and colleagues showing that Nlp is a substrate for both Nek2 and Plk1, and that the in vitro phosphorylation of Nlp by Plk1 is enhanced by Nek2, suggest that Nek2 might prime Nlp for Plk1 (Rapley et al., 2005
). This idea is supported by experiments using the kinase-dead Nek2A, which interferes with Plk1-induced displacement of Nlp from the centrosome (Rapley et al., 2005
). Such interactions with polo kinases might be a conserved ancestral activity because Fin1p, the Schizosaccharomyces pombe Nek2 ortholog (see Fig. 1A), recruits polo kinase (Plo1) to the spindle pole body (Grallert and Hagan, 2002
). However, Fin1p affects the spindle at a later point in the cell cycle, after the metaphase-anaphase transition (Krien et al., 2002
). Intriguingly, it binds only to spindle pole bodies that are more than two cell cycles old and appears to regulate the polarity of the septum initiation network (SIN), a conserved mitotic exit network (Grallert et al., 2004
; Simanis, 2003
).
Nek2 might also regulate the core kinetochore protein Hec1 (for `highly expressed in cancer 1'; also known as Ncd80), which is essential for the organization of stable microtubule plus end binding sites in the outer plate (DeLuca et al., 2005). Prior to metaphase, Hec1 anchors the spindle checkpoint protein Mad1 to kinetochores that have not yet formed stable microtubule attachments (DeLuca et al., 2003
). The Saccharomyces cerevisiae Nek2 ortholog Kin3p and human Nek2 can both phosphorylate Hec1 (human and yeast) at Ser165, and this is essential for the integrity of chromosome segregation (Chen et al., 2002
). In this context, it is notable that Nek2A has also been identified as a Mad1-binding protein, which has lead to speculation about a role for Nek2A in the integration of the spindle checkpoint (Lou et al., 2004
).
Nek2 might be a key player in additional checkpoints. It has been identified as a downstream target of the DNA damage response pathway: DNA damage induced by radiation or chemical agents leads to decreased amounts and activity of Nek2 and a corresponding inhibition of centrosome splitting, presumably contributing to the observed G2 delay (Fletcher et al., 2004). Additionally, Nek2A has been reported to translocate to nucleoli and activate Nek11 during G1-S arrest (Noguchi et al., 2004
). The cellular role(s) of Nek11, which also has two splice variants, remains to be determined.
Proteins in the NIMA/Nek2 clade have thus adopted nuanced roles in the regulation of cell-cycle progression. In general, they appear to be most active during progression through G2 phase and mitosis. Although there is no direct evidence that vertebrate Neks participate in NPC disassembly, the observation that exogenous expression of NIMA in mammalian cells triggers NPC disassembly (Lu and Hunter, 1995b), suggests that regulation of NPC breakdown might be a general role of Nek2-like kinases. Alternatively, it may be an ancestral function lost by Nek2 and retained by another Nek. The well-documented role that vertebrate Nek2 plays in centriole separation might also be an ancestral Nek activity, particularly given that this function is conserved in Dicytostelium and Drosophila (Graf, 2002
; Prigent et al., 2005
).
Notably, the Chlamydomonas Nek family is not represented in the Nek2/NIMA clade. Mitosis in Chlamydomonas is partially closed: nuclear envelope breakdown does not occur and instead the nuclear membrane becomes fenestrated (Johnson and Porter, 1968). It is not known whether partial NPC disassembly occurs during mitosis in Chlamydomonas, but we would predict that it does not. Indeed, given the fenestrations, there would be no need for NPC disassembly. The centrosome-separating activity of Nek2 is also not required in Chlamydomonas, because the centrioles/basal bodies are held together by a different mechanism that does not involve C-Nap1 or Nlp.
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The Nek6/Nek7 clade: components of a mitotic kinase cascade |
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Human Nek6 appears to be required for progression through mitosis: its abundance and kinase activity are increased during mitosis (Belham et al., 2003; Yin et al., 2003
) and interfering with Nek6 function by either expression of kinase-dead Nek6 or depletion of Nek6 by short interfering (siRNA) causes mitotic arrest [at metaphase and pro-metaphase, respectively (Yin et al., 2003
)]. Whether Nek7 also has a role in mitosis is less clear. In vitro studies of recombinant and exogenously expressed Nek6 and Nek7 indicate that the mechanisms of regulation of these two similar kinases might differ dramatically (Minoguchi et al., 2003
), but both appear to be activated by Nek9 [see below (Belham et al., 2003
)]. The targets of Nek6 (and Nek7) remain to be determined.
Although a great deal of work remains to be done before we understand the cellular roles of the proteins in this clade, it appears that they are part of a regulatory cascade that is important for progression through mitosis (see below). We note that this clade does not include representatives from the fungi or from the higher plantsthe two eukaryotic lineages that lack centrioles/basal bodies and cilia. This leads us to speculate that the effects of this regulatory kinase cascade on spindle formation and function are intimately associated with centrioles and possibly cilia. Consistent with this idea, is the finding that the Chlamydomonas ortholog of Nek6, Cnk6p, is in the ciliary proteome (Pazour et al., 2005).
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Nek9: roles throughout the cell cycle? |
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The role of Nek9 might not be restricted to mitosis. It has been shown to localize to the nucleus and associate with the FACT (for `facilitates transcription of chromatin templates') complex, and Nek9-knockdown cells exhibit delayed progression through G1 and S phase, which indicates a role for Nek9 in interphase (Tan and Lee, 2004).
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Nek1 and Nek8: cilia, cell cycle and cystic kidneys |
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The first vertebrate Nek to be cloned, mNek1, was identified in a mouse expression library screened with antibodies to phospho-tyrosine (Letwin et al., 1992). Its kinase domain is 42% identical to that of NIMA (indicative of the well-conserved sequences of the kinase domains of Neks) but the two proteins have divergent C-terminal domains. Nek1 is larger than NIMA (1258 amino acids compared with 699) and the Cterminus of Nek1 includes a larger coiled-coil domain than NIMA, although both contain PEST motifs (O'Connell et al., 2003
). mNek1 is highly expressed in testes and ovaries (Arama et al., 1998
; Letwin et al., 1992
), as well as in peripheral and motor neurons (Arama et al., 1998
), which suggested it might function in meiosis and/or differentiation (Arama et al., 1998
; Letwin et al., 1992
). However, Upadhya and colleagues (Upadhya et al., 2000
) subsequently reported that mutations in mNek1 are the causal defects in two allelic mouse models of progressive polycystic kidney disease, kat and kat2J (for `kidney, anemia, testis').
Renal cysts are characteristic of a wide range of diseases, many of which have multi-organ pathology (Wilson, 2004). The kat mice show a progressive increase in the size and number of cysts in the kidney cortex. This is accompanied by male sterility as a result of testicular hypoplasia, dilation of the ventricles of the brain, multiple large cysts in the choroid plexus, very small olfactory bulbs, facial dysmorphism and runting (Janaswami et al., 1997
; Vogler et al., 1999
). Given the similar pathology in the kidney and the choroid plexus, Nek1 could play similar roles in renal and choroid epithelial cells, which when compromised lead to aberrant cell proliferation and fluid accumulation (Janaswami et al., 1997
). But what those roles might be and what cellular defects caused by Nek1 mutation might trigger the other aspects of the pleiotropic phenotype, remain to be established.
Several proteins that bind to Nek1 have been identified. Yeast two-hybrid assays using an mNek1 kinase domain, including an inactivating G13R mutation as bait, identified a leucine-zipper protein termed Nurit that is only expressed in testis and appears to be involved in late spermiogenesis (Feige et al., 2002). Studies using the central coiled-coil region of human Nek1 as bait identified 11 proteins (Surpili et al., 2003
). These include KIF3A, a ubiquitously expressed kinesin motor that is important for ciliogenesis, neuronal polarity and the establishment of laterality during early embryonic development, and whose kidney-specific knockout results in the proliferation of renal cysts (Lin et al., 2003
); tuberin, a tumor suppressor that plays an important role in the membrane localization of polycystin 1, mutations in which are responsible for the most common form of polycystic kidney disease (Kleymenova et al., 2001
); and, finally, several proteins that participate in DNA repair pathways (Surpili et al., 2003
). This is consistent with the report by Polci and colleagues (Polci et al., 2004
) showing that mNek1 expression and activity are stimulated following DNA damage. The in vivo veracity and the specific cellular roles the various interacting proteins play in the physiological functions of Nek1 remain to be determined. Significantly, mutations in another Nek, Nek8, have since been shown to cause renal cysts in a mouse model of recessive juvenile-onset cystic kidney disease, jck [for `juvenile cystic kidney' (Liu et al., 2002
)].
The Nek8 protein (703 residues) is smaller than Nek1 and lacks a coiled-coil domain and PEST motifs, but contains an RCC1 (regulator of chromosome condensation) domain (see O'Connell et al., 2003). RCC1 domains form ß-propeller structures similar to, but distinct from, WD40 domains. The role of the RCC1 domain in Nek8 is not known; however, a G448V substitution (within the RCC1 domain) is responsible for the jck phenotype (Liu et al., 2002
). Overexpression of mutant forms of Nek8 (including G448V) in tissue culture cells leads to the formation of enlarged multinucleate cells and reduced numbers of actin stress fibres, although tubule cells in jck mice are not multinucleate. These and other in vitro observations led Liu and colleagues (Liu et al., 2002
) to speculate that the cellular role of Nek8 is related to regulation of the cytoskeleton. Indeed, overexpression of a kinasediminished hNek8 mutant in U2-OS cells affects the expression of actin (Bowers and Boylan, 2004
). A proteomic study of the renal cysts from jck mice revealed overexpression of galectin-1, sorcin and vimentin (Valkova et al., 2005
). We are clearly a long way from understanding the cellular role of Nek8.
The cellular basis of renal cyst formation is not understood, but recent evidence indicates that defective signaling from the primary cilium of epithelial cells is an important factor (reviewed by Pazour, 2004, Pazour, 2004
). How defective ciliary signaling might cause renal cyst formation is unknown. Cyst formation requires several changes to the epithelium, and the process by which these epithelial cells re-enter the cell cycle could be analogous to transitions that normally occur during development and tissue remodeling. For example, in developmental epithelial-mesenchyme transitions, epithelial cells (many of which are ciliated) partially dedifferentiate (D'Souza-Schorey, 2005
). In jck mice at 2-3 weeks of age (i.e. prior to the development of kidney cysts), the integrity and structure of the tubular epithelial basal membrane is disrupted and epithelial cells occasionally detach from the basement membrane of collecting ducts (Liu et al., 2002
). In this context, it is interesting to note that the mammalian Par complex, required for proper epithelial cell polarization, is required for the assembly of, and localizes to, primary cilia (Fan et al., 2004
). We predict that Nek family members participate in regulation of these events.
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Coevolution of Nek kinases and centrioles |
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Examination of the genomes of several organisms reveals a correlation between the number of Neks in a particular organism and whether or not it has ciliated cells (Fig. 2). Drosophila and Caenorhabditis elegans have ciliated cells and thus might be expected to have more Neks than the higher plants, represented by Arabidopsis, which do not have ciliated cells. However, we posit that, because the only ciliated cells in Drosophila and C. elegans are terminally differentiated, these organisms do not have to coordinate cilia and the cell cycle (i.e. they do not have centrioles that serve as both basal bodies and microtubule-organizing centers). Indeed, employing a binary approach in which `1' is assigned to organisms that possess ciliated cells that re-enter the cell cycle and `0' is assigned to organisms that do not, we have tested this hypothesis by using the evolutionary software Continuous v1.0d13 PPC (Pagel, 1994). The result of comparing a model in which the number of Nek genes and the ability of ciliated cells to divide evolve independently with an alternative model in which the two traits evolve in a correlated fashion strongly supports our hypothesis (P=0.01). We propose that the large number of Neks in the higher plants is a consequence of an independent expansion involving substantial sub- and neo-functionalization. In other words, in higher plants, this family of kinases may have been coopted and expanded in the service of cellular activities unrelated to their ancestral functions. Consistent with this is the finding that higher-plant Neks fall into a clade distinct from the Neks of other organisms (Fig. 1C).
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Conclusion/Perspectives |
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Here, we have proposed that expansion of the Nek family accompanied the evolution of a robust and complex system for the coordination of progression through the cell cycle with cilia, basal bodies and centrioles. Such a connection is consistent with the role of Neks in the development of polycystic kidneys in mice; however, so far, the only link between all three parameters is provided by Chlamydomonas. The Neks Fa2p and Cnk2p are ciliary proteins that have ciliary functions, and both proteins also affect cell-cycle progression (Mahjoub et al., 2004; Bradley and Quarmby, 2005
). In addition, there is increasing evidence from both Chlamydomonas and Tetrahymena that the Nek family play important roles in the regulation of ciliary length (Bradley and Quarmby, 2005
) (J. Gaertig, personal communication; J. D. Parker and L.M.Q., unpublished). These data lead us to predict that some of the mammalian Neks localize to cilia and that, in addition to affecting cell-cycle progression, mammalian Neks, like their microbial brethren, regulate ciliary function.
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Acknowledgments |
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