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Stress-associated p38 and JNK mitogen-activated protein (MAP) kinase signaling cascades trigger specific cellular responses and are involved in multiple disease states. At the root of MAP kinase signaling complexity is the differential use of common components on a context-specific basis. The roundworm Caenorhabditis elegans was developed as a system to study genes required for development and nervous system function. The powerful genetics of C. elegans in combination with molecular and cellular dissections has led to a greater understanding of how p38 and JNK signaling affects many biological processes under normal and stress conditions. This review focuses on the studies revealing context specificity of different stress-activated MAPK components in C. elegans.
Sydney Brenner chose the roundworm Caenorhabditis elegans as a model biological system to address questions regarding development and neurobiology (1). Because of its stereotyped development, short life cycle, transparency, ease of genetic manipulation, and conservation of genes with higher mammals, C. elegans provides many advantages to characterize the function of genes. Studies over the past four decades using C. elegans have revealed fundamentally conserved principles underlying many biological processes (2,–4). For example, isolation and characterization of uncoordinated mutants or drug-resistant mutants led to the discovery of genes and mechanisms functioning in the nervous system (1, 5). The evolution and intricacies of genetic screens in C. elegans have been reviewed in Ref. 6. Here we review the approaches used to uncover the in vivo roles of stress-activated MAP3 kinases and discuss how these findings have advanced our understanding of stress responses in select cellular processes.
MAPKs act as central signaling hubs, transducing extracellular cues to control cellular processes such as proliferation, differentiation, apoptosis, and migration (7). Due to their multifaceted roles and importance in many cellular processes, their malfunctioning is associated with a wide array of human diseases, such as atherosclerosis and tumorigenesis (8, 9). MAPKs can be classified into three families; the ERK, p38, and JNK classes, originally defined based on kinase activity, target specificity and sequence homology. Early studies on p38 and JNK, mainly in mammalian cell lines, showed that they are predominantly activated by adverse stimuli such as osmotic stress, heat shock, or cytokines (7). This notion triggered a misnomer in the term “stress-activated MAP kinase.” In vivo evidence in genetically tractable models did not support a solely stress-dependent role for JNK and p38, as null mutants generally resulted in severe developmental defects (10,–13). It is now widely known that JNK and p38 regulate both normal and stress-associated signaling (7).
MAPK cascades consist of a sequential activation of kinase substrates (MAPKKK/MAPKK/MAPK) culminating in the phosphorylation and activation of the terminal MAPK. The C. elegans genome encodes four JNK MAPK homologs, JNK-1 (67% identity to JNK1), KGB-1 (48%), KGB-2 (51%), and C49C3.10 (31%), which share a conserved TPY activation motif, and three p38 MAPK homologs, PMK-1 (64% identity to MAPK14), PMK-2 (56%), and PMK-3 (42%), which share the TGY or TQY activation motif (Fig. 1). The TQY motif is unique to nematodes and several plant species (14, 15). C. elegans homologs of stress MAPKKs include four groups, those similar to MKK7 (mek-1, jkk-1), MKK4 (mkk-4, sek-3, sek-6), MKK3/6 (sek-1), and MKK3 (sek-4, sek-5). Multiple homologs of the stress MAPKKK family are also found, including DLK/LZK (dlk-1), ASK1 (nsy-1), TAK1 (mom-4, Y105C5A.24), TAO (kin-18), MLK (mlk-1), and ZAK (zak-1) (16). The presence of p38 and JNK orthologs in C. elegans offers the opportunity to exploit the power of genetics to characterize these putative stress pathways in vivo. A general theme in stress-activated MAPK signaling is their context specificity, which is accomplished through integrating different components to activate distinct cellular responses (Figs. 2 and and3).3). The remarkable level of context specificity is somewhat paradoxical considering the broad expression pattern of the majority of p38 and JNK components (Fig. 1). Interestingly, the initial studies of stress-activated MAPK signaling in C. elegans came from observations of developmental and non-stress-related phenotypes (16).
The identification of C. elegans homologs of the JNK signaling pathway was born out of the need for an in vivo model to study the complexities of MAPK pathways. From an evolutionary perspective, the JNK and p38 signaling pathways are thought to have been derived from a duplication event in the ancestral yeast hyper-osmolarity Hog1p kinase pathway and hog1 mutants are defective in osmotic sensing (17, 18). A C. elegans cDNA library was expressed in yeast hog1 mutants with the reasoning that conserved components of the p38/JNK pathways would rescue osmo-regulatory defects (19). This strategy led to the identification of jnk-1 and jkk-1 as JNK and its upstream MAPKK, respectively. jnk-1 and jkk-1 are expressed in the nervous system (Fig. 1). Complete loss of function mutants of jkk-1 and jnk-1 exhibit normal growth and nervous system architecture but display movement defects, which was shown to be due to their function in GABAergic inhibitory motor neurons (19, 20). Another study identified mek-1 based on homology to MKK7 (21). Animals overexpressing a phospho-mimetic activated form of MEK-1 displayed behavioral phenotypes such as pharyngeal pumping defects, uncoordinated movement, and defective egg laying. A mek-1 deletion mutant was generated using transposon mutagenesis, and reported to enhance the feeding defects of several Eat mutants, which are defective in pharyngeal pumping (21). Recent analysis revealed that the original mek-1(ks54) mutant strain contains a linked mutation in sek-1(qd127), a closely related MAPKK,4 and this genetic background will be denoted as mek-1(sek-1) throughout the text. Although the precise roles of mek-1, jnk-1, and jkk-1 in locomotion and feeding remain to be determined, these studies provide a glimpse of the function of the C. elegans JNK kinase pathway in the nervous system.
A developmental role for KGB-1 (kinase and GLH-binding) was identified in the germline of C. elegans. Germ cells and their precursors contain RNA-protein complexes termed P granules, which are important for fertility (22, 23). A key class of germline granule proteins is the germline RNA helicase (GLH) family (24). KGB-1 was initially identified in a yeast two-hybrid screen for GLH-binding proteins (25). KGB-1 can bind and phosphorylate GLH-1, which leads to degradation of phosphorylated GLH-1 (25, 26). A kgb-1 null mutant, obtained by targeted deletion, showed extra germ cells, increased number of P granules, and temperature-sensitive sterility (25). RNAi-mediated knockdown of glh-1 in kgb-1 mutants partially rescued the P granule number and temperature-sensitive sterility (26). These studies suggest a model in which KGB-1 activity negatively regulates GLH-1 and the steady state level of P granules to maintain fertility. To date the specific MAPKKK or MAPKK upstream of KGB-1 in P granule formation remains to be determined.
Roles for the p38 signaling pathway were first revealed from screens focusing on the developing nervous system (27, 28). One member of a pair of bilaterally symmetric AWC sensory neurons expresses the str-2 odorant receptor in a stochastic manner (29, 30). A mutagenesis screen was designed to identify factors regulating AWC asymmetry. Analyses of mutants in which str-2 was expressed in both AWC neurons revealed a loss of function allele for nsy-1, the homolog of the mammalian ASK1 MAPKKK (27). Based on a similar AWC phenotype, the MKK3/6 sek-1 was subsequently placed downstream of nsy-1 (31). Although these early observations suggested that a p38 MAPK might act downstream of nsy-1 and sek-1, definitive evidence was only recently provided when an unexpected finding revealed functional redundancy of pmk-1 and pmk-2 (32). The three pmk genes are encoded by a single polycistronic transcript (operon), precluding the generation of double mutants by traditional genetic crosses. A strain with mutations in both pmk-1 and pmk-2 was serendipitously identified in a screen searching for suppressors of the pmk-1 loss of function phenotype following bacterial infection (32, 33). Double mutants of pmk-1 and pmk-2 recapitulated the AWC phenotype of sek-1 and nsy-1 (32). These data provide a model where a NSY-1/SEK-1/PMK-1 and PMK-2 cascade acts during neuronal development to regulate AWC asymmetry (27, 32). Moreover, the activation of this p38 kinase cascade is regulated in part by calcium, via calmodulin kinase II, as well as the conserved protein TIR-1 (27, 31, 34). The mammalian ortholog of TIR-1, SARM1, has been studied for its vital importance during axon degeneration and has been shown to activate a MAPK cascade following axon injury (35). In addition, PMK-1 and PMK-2 were shown to act redundantly downstream of TIR-1/NSY-1/SEK-1 to induce TPH-1 expression in the ADF neuron following exposure to bacteria (32, 36, 37).
PMK-3 and its upstream regulators were similarly defined in a neurodevelopmental context. The E3 ubiquitin ligase RPM-1 regulates synapse development such that rpm-1 null mutants display disorganized synapses and reduction of synapse number (38, 39). To identify substrates for RPM-1, a large-scale suppressor screen took advantage of a synthetic paralysis when rpm-1(lf) was in combination with other synaptogenesis mutants (28). Mutant worms that suppressed the synthetic locomotor defect were isolated and shown to suppress the synapse defects of an rpm-1 single mutant. Characterization of these suppressors led to the identification of loss of function mutations in dlk-1, mkk-4, and pmk-3. Genetic epistasis analyses further supported that these three kinases constitute a linear DLK-1/MKK-4/PMK-3 pathway. Moreover, cell biological and biochemical evidence showed that DLK-1 is a substrate of RPM-1 (28). Subsequent studies of other suppressor mutations led to the identification of two downstream targets, mak-2 and cebp-1 (40). MAK-2 is the homolog of MAPKAPK2 (MK2), and acts downstream of PMK-3. CEBP-1 is a member of the C/EBP (CCAAT/enhancer-binding protein) transcription factor family, and represents a novel transcription factor downstream of MAK-2. During synapse development, the activity of this PMK-3 kinase cascade is controlled through ubiquitin-mediated degradation of DLK-1 by the RPM-1 E3 ubiquitin ligase.
Overall, these studies show that distinct p38 and JNK MAPK cascades regulate a diverse class of “normal” biological processes during development and nervous system function (Fig. 2). The third JNK homolog KGB-2 shows 84% identity with KGB-1. So far the only reported roles for KGB-2 are in excess carbon dioxide (hypercapnia)-induced fertility defects and a slight negative role in axon injury response (41, 42). Presently, little is known about the function of the fourth JNK homolog C49C3.10.
The term “stress-response pathway” encompasses a wide range of cellular functions that protect an organism against harmful conditions. Types of stress include elevated temperature, toxin exposure, cellular damage, and infiltration by pathogens. Each type of stress has unique consequences and requires a different repertoire of subcellular signaling pathways to properly buffer their effects. Although the upstream and downstream components differ, and often the specific MAPK cascade varies, ultimately a MAPKKK/MAPKK/MAPK cascade is activated to trigger specific cellular and organismic responses (7). Studies in C. elegans have shed light on context specificity in stress-activated MAPK signaling (Fig. 2). Below, we will highlight how C. elegans has been used to characterize these MAPK-dependent cellular responses in infection, axon injury, and environmental stress.
Innate immunity, or host defense, is a mechanism that is conserved across evolution for a host organism's response to pathogens (43). The functional conservation of immune response in C. elegans has provided a powerful platform to rapidly screen genes and to dissect mechanisms regulating innate immunity (44, 45). These studies have led to the discovery of a myriad of novel signaling pathways associated with stress-activated MAPK activation and their downstream targets (46).
It is fitting that the first investigation of innate immunity using genetic screening in C. elegans yielded the association of p38 signaling to a stress response (33). The human opportunistic pathogen Pseudomonas aeruginosa causes an intestinal infection and eventual death of the worm (47). This response offers a simple screening strategy to identify genes involved in protective mechanisms (33). Wild-type worms begin to succumb to infection at 34 h, and mutant worms with enhanced susceptibility to P. aeruginosa (Esp) die between 16 and 30 h. The death of the worms occurs after they become fertile adults, and thus progeny can be salvaged and propagated to establish strains. esp-2 and esp-8 mutations were found to affect sek-1 and nsy-1, respectively. pmk-1 mutants were also shown to exhibit an Esp phenotype, although not identified in the screen. Therefore following P. aeruginosa infection, a protective NSY-1/SEK-1/PMK-1 pathway is activated. As mentioned earlier, pmk-1 and pmk-2 function redundantly during olfactory neuronal development (32). However, double mutants of pmk-1 and pmk-2 did not exacerbate the pmk-1 phenotype in the intestine following infection. Interestingly, pmk-2 expression in the intestine is under negative regulation by a set of microRNAs via its 3′-UTR. Removing the 3′-UTR of pmk-2 caused its expression in the intestine, which was sufficient to rescue the Esp phenotype of pmk-1 mutants. The use of 3′-UTR elements to regulate tissue-specific expression of pmk-2 provides a mechanism that endows context specificity to p38 paralogs. A recent study has revealed a similar regulatory theme utilizing 3′-UTR elements in cultured human cells (48).
The fungal pathogen Drechmeria coniospora infects C. elegans by adhering to and penetrating its cuticle, resulting in epidermal damage and ultimately organismal death (49). Studies of D. coniospora infection uncovered roles for the same p38 pathway used in the intestine following P. aeruginosa exposure (50). To identify the factors that initiate the epidermal innate immune cascade in vivo, a clever transcriptional reporter using green fluorescent protein driven by the promoter of the antimicrobial peptide (AMP) gene nlp-29 was developed to detect immune activity upon D. coniospora infection. Several Nipi (no induction of peptide after Drechmeria infection) mutants were identified, and found to affect the entire NSY-1/SEK-1/PMK-1 cascade (50). Through a series of elegant genetic experiments, a G-protein-dependent cascade consisting of the α/β G-protein subunits of GPA-12/RACK1 via EGL-8/TPA-1/TIR-1 (phospholipase C, protein kinase C, and the Toll-1 interleukin receptor domain adaptor protein) was shown to act upstream of NSY-1/SEK-1/PMK-1 (51, 52). Following bacterial infection, the protein kinase D ortholog, dkf-2, was shown to act upstream of tir-1 to activate PMK-1 (53). In a subsequent study, the G-protein-coupled receptor dcar-1 and 4-hydroxyphenyllactic acid (HPLA) were identified as receptor and ligand upstream of GPA-12 activation following fungal infection (54). HPLA is generated by epidermal damage, rather than by the pathogen, providing a link between the similarities in MAPK signaling in wounding and infection (50, 55). These studies illustrate the regulation of the context specificity of the same p38 MAPK cascade in bacterial and fungal infection through different upstream components.
Neurons are subject to many kinds of stress and damage throughout their lifetime. In the mammalian central nervous system, injured axons lack the ability to regenerate, largely due to a combination of inhibitory mechanisms involving both intrinsic and extrinsic factors (reviewed in Ref. 56). C. elegans neurons display a robust regeneration response following precise severing of single, stereotyped axons using a high-powered laser (57, 58). Although axon regeneration is observed in most neurons, the degree to which an axon regenerates is variable. To define molecular mechanisms underlying axon injury-induced stress, a large-scale axon regeneration screen using genetic mutants was performed, revealing multiple conserved pathways (59). Among them is the DLK-1/MKK-4/PMK-3 cascade, activation of which is necessary to initiate axonal regrowth (40, 60). As mentioned early, this p38 kinase cascade is tightly regulated by protein ubiquitination during synapse development (28). Axon injury triggers rapid and transient calcium influx (61), which regulates DLK-1 activity via an auto-regulatory mechanism involving protein isoform binding (62). As described below, this same p38 kinase cascade has also been identified in studies of multiple neuronal insults.
In parallel to studies on laser-induced axon injury, p38 and JNK MAPK cascades were also implicated in regeneration by studies of unc-70/β-spectrin mutants (42, 63). Cytoskeletal defects in unc-70 mutants make their axons, which frequently break upon mechanical stress caused by animal movement, fragile. The broken axons in unc-70 mutants can spontaneously regrow (63). Taking advantage of the non-invasive nature of the axon breaks, a large-scale RNAi screen targeting conserved molecules was performed (42, 60). The initial studies revealed dlk-1, acting through pmk-3, to be required at the time of injury, where it regulates the formation of the growth cone, a specialized structure required for axon growth (60). Steered by these observations, studies of additional genes from this screen revealed the roles of a KGB-1/JNK kinase cascade, composed of mlk-1, mek-1(sek-1), and kgb-1, in axon regeneration. Mutants in this JNK pathway showed impaired axon regrowth to variable degrees, with kgb-1 being most severe (64). The dual phosphatase vhp-1 is a negative regulator of both p38 and JNK signaling (65, 66). Loss of function mutants of vhp-1 showed improved regeneration (64). pmk-3 vhp-1 double mutants displayed a modest improvement in regeneration when compared with pmk-3 alone, suggesting that increasing kgb-1 activity may compensate for loss of pmk-3. Conversely, vhp-1 kgb-1 double mutants regenerated quite well, indicating that pmk-3 appears to better compensate for the loss of kgb-1 than vice versa. Thus, axon regeneration provides a specific context in which both p38 and JNK exert their effects, albeit p38 being the predominant MAPK.
Null mutations in vhp-1 cause larval lethality, which can be suppressed by null mutations in mlk-1, mek-1, kgb-1, dlk-1, or pmk-3 (64, 65). A genome-wide RNAi screening approach was undertaken to identify suppressor of vhp-1 (Svh) genes (67, 68). svh-1 encodes a predicted extracellular protein with a structure similar to that of the mammalian hepatocyte growth factor (HGF) and macrophage-stimulating protein (MSP). svh-2 encodes a receptor tyrosine kinase homologous to the HGF and MSP receptors. Because vhp-1 regulates MAP kinases in axon regeneration, the function of svh-1 and svh-2 during this process was examined (40, 60, 64). Loss of function mutants in either gene showed impaired regeneration capacity, resembling mlk-1 mutants (40, 60, 68). SVH-2 could bind MLK-1 but not DLK-1 in vitro (68). svh-2 mutants also showed a marked decrease in phospho-KGB-1. Thus, svh-1 and svh-2 likely provide a layer of specificity in controlling the KGB-1/JNK pathway, independently of PMK-3 in axon injury response. However, recent evidence suggests that there may be crosstalk between the KGB-1 and PMK-3 cascades, as the transcription of svh-2 appears to be regulated by CEBP-1, a downstream factor of PMK-3 (69). The exact roles for transcriptional targets of CEBP-1 during axon regeneration have yet to be determined. Nonetheless, these studies implicate a growth factor as a potential intermediate between p38 and JNK kinase pathways during axon regrowth.
Microtubule dynamics plays an important role in axon regeneration in both C. elegans and vertebrate injury models (59, 70, 71). The touch neurons PLM and ALM are microtubule-rich and use specific microtubules to transmit mechanical stimuli (72). Treatment with colchicine, a drug that can cause microtubule depolymerization or damage to microtubule cytoskeleton, reduced overall gene expression in touch neurons (73). To dissect how microtubule disruption and gene expression intersect, an elegant screen using a short-lived GFP reporter was performed. Analyses of several Colchicine-resistant (Cre) mutants identified dlk-1 and cebp-1. Loss of function of pmk-3 showed a similar Cre phenotype, whereas mkk-4 mutants exhibited a much milder phenotype when compared with pmk-3 or dlk-1, pointing to possible redundancy at the MAPKK level (73). C. elegans MAPKK genes are clustered on the X chromosome, complicating examination of double mutant animals. Nonetheless, MAPKK redundancy may provide an interesting context specificity following colchicine treatment, contrasting axon regeneration, which is strongly dependent on mkk-4 (40).
The day-to-day life of any organism is stressful with a near constant bombardment of environmental stresses ranging from toxins, to nutrient availability, to temperature. All of these stress paradigms have been studied extensively in vivo using C. elegans as a model and have greatly informed on the biology of these processes. Due to the vast literature on the subject of environmental stress and C. elegans, we will focus on stress-activated MAPK signaling in nutrient deprivation and oxidative stress.
Long-term nutrient deprivation or malnutrition has a detrimental impact on organismal viability. Paradoxically, it has been shown that modest nutrient deprivation or dietary restriction increases lifespan in vertebrate and invertebrate models (74,–76). In C. elegans, lifespan and diet intersect via the insulin signaling pathway, with mutants in genes such as the insulin receptor daf-2 increasing lifespan (77,–79). JNK signaling has also been shown to regulate longevity and interact with the insulin signaling pathway (80,–82). Intermittent fasting (IF) is a paradigm involving transient exposure to nutrient sources and increases lifespan of wild-type C. elegans in an insulin signaling-dependent manner (83). Mutants in kgb-1, but not kgb-2 or jnk-1, abrogated IF-mediated lifespan increase (84). This lifespan phenotype of kgb-1 was independent of previously reported developmental/fertility phenotypes associated with P granule formation. Phosphorylation of KGB-1, which was abolished in mek-1(sek-1) mutants, was observed within 30 min of starvation and maintained for 9 h. Single mutants in the MAPKKK's mlk-1 and nsy-1 both exhibited partial suppression of IF-dependent lifespan extension; however, double mutants of mlk-1 and nsy-1 did not completely recapitulate kgb-1 mutants, suggesting additional upstream regulators. These observations support a model where following nutrient restriction by intermediate fasting, a KGB-1 cascade is required to mediate lifespan extension; however, regulation at the MAPKK and MAPKKK remains to be determined. A major factor in nutrient deprivation-induced changes in longevity is thought to stem from oxidative stress produced as a byproduct of metabolism (85, 86).
Oxidative stress is the result of accumulation of reactive oxygen species (ROS), which in turn damage cellular constituents (87). The activation of JNK signaling was shown to occur under conditions of heavy metal stress (20, 21); however, the role of stress-activated MAPK signaling following treatment with compounds that induce ROS was unknown. Treatment of worms with arsenite, a toxic ROS-producing compound, induced a robust phosphorylation of PMK-1, induction of oxidative stress-responsive genes, and eventual lethality (88). The activation of PMK-1 following arsenite treatment was dependent on SEK-1 but independent of NSY-1, differing from the NSY-1/SEK-1/PMK-1 cascade used during infection and osmotic stress (33, 50, 89). Both sek-1 and pmk-1 mutants exhibited an enhanced sensitivity and lethality to arsenite treatment and prevented the induction of gcs-1, an oxidative stress reporter, in the intestine (88). pmk-1 mutants were not as sensitive as sek-1 mutants, suggesting a potential redundancy in MAPK usage. gcs-1 expression is predominantly regulated by the transcription factor SKN-1, which translocates to the nucleus of intestinal cells following oxidative stress (90). SKN-1 can be phosphorylated by PMK-1 in vitro, and this phosphorylation is pivotal for its nuclear localization in vivo, as nuclear localization of SKN-1 was significantly impaired in sek-1 and pmk-1 mutants (88). Under another stress context, the nuclear localization of SKN-1 was shown to occur in an NSY-1/SEK-1/PMK-1-dependent manner in the intestine following bacterial infection (91). The upstream adaptor protein TIR-1 was dispensable for SKN-1 localization, which contrasts its requirement for organismal viability after P. aeruginosa exposure (52). In addition to SKN-1, following infection, PMK-1 was shown to phosphorylate and activate the transcription factor ATF-7 (92). These studies show that unique upstream components activating PMK-1 induce SKN-1 activation following toxin and bacterial exposure.
The evolution of C. elegans as a model system has seen the analysis of complex behavioral and cell-specific processes. Recent studies have uncovered additional roles of stress-activated MAPK cascades in multiple behaviors and cellular function, with cell type- and behavior-dependent modification. For example, the avoidance of high CO2 environments and pathogens was shown to be mediated by MOM-4/MKK-4/PMK-3 in the BAG neuron (93). In contrast, the aversive reaction to microbial exposure is mediated by a MLK-1/MEK-1(SEK-1)/KGB-1 pathway (94). Olfactory memory in C. elegans allows for the association of cues with positive or negative experiences. The loss of these memories was shown to proceed through UNC-43/TIR-1/NSY-1/SEK-1/JNK-1 (95). Interestingly, olfactory learning is mediated in part by the AWC neurons, which use a similar pathway during development (27, 96). Advances in microscopic techniques have also allowed for the study of sub-cellular processes and structures that were previously not possible in the worm. In a screen for mutants defective in dye filling, DLK-1/PMK-3 were identified to affect cilia length, via regulation of RAB-5 endosomes (97). The MAPKK(s) acting between DLK-1 and PMK-3 in this role remains to be identified.
Forty years out from the first published screen in C. elegans (1), the use of forward genetics remains a powerful approach to dissect biological processes at both the organismal and the cellular level. Specifically, the use of C. elegans models including infection, axon injury, and environmental stress has revealed stress-associated MAPK signaling components. However, there is still much to be understood about how these pathways truly function in vivo. A resounding theme in both non-stress and stress conditions is the context-specific nature for these pathways (Figs. 2 and and3).3). Recent studies have highlighted redundancy and crosstalk between p38 and JNK signaling components that may play an important role in regulating their context specificity (32, 64). Moreover, functions have yet to be revealed for several MAPK cascade components. For example, the roles of kgb-2 have yet to be associated with any biological process, and it may function as a safeguard in the JNK cascade. CRISPR/Cas9-mediated genome editing (where CRISPR stands for clustered regularly-interspaced short palindromic repeat) can now be employed to manipulate potential redundant MAPKKs that all clustered on the X chromosome. Teasing apart unique cell type- and stress-specific aspects of MAPK signaling pathways will help inform on their overall roles, with hopes that C. elegans continues to serve as a platform to translate meaningful in vivo findings into relevant interventions for human conditions that exhibit de-regulated MAPK signaling.
We thank members of the Jin and Chisholm laboratories for insightful discussions and comments on the manuscript and D. Kim for communication of unpublished results.
*This work was supported by National Institutes of Health Grant NS 035546 (to Y. J.). This is the second article in the Thematic Minireview series “Cell Signaling in Simple Organisms.” The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
4K. Reddy and D. Kim, personal communication.
3The abbreviations used are: