MAPK Pathway in Caenorhabditis elegans
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MAPK Pathway in Caenorhabditis elegans

The MAPK (Mitogen-Activated Protein Kinase) pathways are highly conserved signaling cascades that convert extracellular signals into various outputs. Each pathway is composed of three classes of protein kinase: MAPK, MAPKK (MAPK Kinase) and MAPKKK (MAPK Kinase Kinase). MAPK is activated by phosphorylation of specific tyrosine and threonine residues by a family of dual-specificity protein kinase MAPKKs. MAPKK is in turn activated by phosphorylation of serine and serine/threonine residues by a family of upstream MAPKKKs. Each of these upstream components plays a role in multiple cell signaling processes. The ERKs (Extracellular-signal Regulated Kinases), SAPK/JNKs (Stress-Activated Protein Kinases/c-Jun N-terminal Kinases), and p38 are the three best characterized subfamilies of MAP kinases and have representatives in all eukaryotes. In invertebrates, the corresponding MAPK pathway has been elucidated through the genetic analysis of Drosophila and Caenorhabditis elegans, which have proven to be excellent organisms for the genetic analysis of cell signaling. In C. elegans, the ERK1/2 pathway, consisting of lin-45, mek-2, and the ERK ortholog mpk-1, plays an important role in vulval development. More recently, components of the JNK pathway, jkk-1 and jnk-1, have been identified in C. elegans as part of a neuronal pathway controlling coordinated movement. Also, mek-1, a C. elegans homolog of a MEK in stress-sensitive pathways, plays a role in a nematode stress response. Three p38 isoforms in C. elegans termed p38 Map kinases 1–3 (pmk-1, pmk-2, and pmk-3) have been identified recently (Ref.1).

In C.elegans vulva development, the mpk-1 MAPK pathway mediates the induction of vulval cell fates. The genes required for vulval induction include the lin-3 TGF-Alpha (Transforming alpha-like Growth Factor), the let-23 EGF Epidermal Growth Factor)-receptor-like transmembrane tyrosine kinase, the sem-5 adaptor protein, let-60 Ras, and the lin-45 Raf serine/threonine kinase.  The Ras homolog of C. elegans (let-60) is a key player in the signal transduction pathway that controls the choice between vulval and epidermal differentiation in response to extracellular signals. The pathway downstream of let-60 is composed of a MAPK module employing the MKKK homolog lin-45, the MEK homolog mek-2, and the ERK homolog mpk-1/Sur-1. mpk-1 directly regulates both the lin-31 winged-helix and the lin-1 Ets transcription factors to specify the vulval cell fate. lin-31 and lin-1 act genetically downstream of mpk-1, and both proteins can be directly phosphorylated by MAP kinase. lin-31 binds to lin-1, and the lin-1/lin-31 complex inhibits vulval induction. Phosphorylation of lin-31 by mpk-1 disrupts the lin-1/lin-31 complex, relieving vulval inhibition. Phosphorylated lin-31 may also act as a transcriptional activator, promoting vulval fates. lin-31 is a vulval-specific effector of mpk-1, while lin-1 acts as a general effector. The partnership of tissue-specific and general effectors may confer specificity onto commonly used signaling pathways, creating distinct tissue-specific outcomes. Another Raf1 homolog, ksr-1, has also been isolated. It is, however, unclear whether ksr-1 lies downstream of let-60 Ras or if it is part of a MAPK pathway that functions in parallel to the lin-45/sur-1 pathway (Ref.2).

JNK of the MAPK superfamily is involved in various stress responses and apoptosis in mammal. In C.elegans, there are at least two different JNK activators, mkk-4/sek-1 and mkk-7/jkk-1. The former can activate both the JNK and p38 subgroups of the MAPK superfamily, whereas the latter is specific for JNK. The first JNK cascade is composed of jnk-1 (MAPK) and jkk-1 (MAPKK). The jnk-1 pathway functions in type-D GABAergic (GABA, Gamma-aminobutyric acid) motor neuron and modulates coordinated locomotion. The C. elegans unc-16 gene encodes a protein homologous to mammalian JSAP1/JIP3, which acts as a scaffold protein in the JNK pathway by binding with mlk (MAPKKK), mkk-7 (MAPKK) and jnk-3 (MAPK). Like JSAP1/JIP3, unc-16 physically interacts with jnk-1 and jkk-1, forming a JNK signaling module. jnk-1 pathway containing unc-16 regulates synaptic vesicle localization. Besides, mek-1, a C. elegans homolog of a MEK in stress-sensitive pathways, also plays a role in a C.elegans stress response (Ref.3).

The evolutionarily conserved p38 MAPK cascade is an integral part of the processes of the response to a variety of environmental stresses. Signals received at the cell surface are relayed into the nucleus, where p38 MAPK modulates the activities of a subset of transcription factors. However, little is known about what lies downstream of the p38 MAPK pathway in the stress response in whole animals.  There are three genes, pmk-1, pmk-2 and pmk-3 that encode p38 MAPKs in C. elegans.  These three proteins appear to lie within an operon, allowing for the transcription of three highly related proteins from a single promoter. Their single promoter is active throughout the length of the intestine and the kinases are activated by osmotic stresses when expressed in mammalian cells. pmk-1 and pmk-2, which share the greatest identity to mammalian p38, are selectively phosphorylated and activated by only one of the three MEK family members that recognize mammalian p38s. A distinguishing feature of MAP kinases is the conserved TXY motif in the activation loop, which includes the two sites phosphorylated to activate the kinases. In the case of p38, the intervening residue X is glycine. This motif is conserved in pmk-1 and pmk-2. pmk-3 contains Q at this position. TQY does not match the motif for any characterized MAP kinase. The MAPK-kinase-kinase that function upstream of pmk-1 are sek-1 and nsy-1, respectively. nsy-1 and sek-1 act downstream of unc-43, a Ca2+/calmodulin dependent kinase, in the nsy pathway. Calcium signaling through the voltage dependent calcium channel unc-2/36, unc-43/CamKII and nsy-1/ASK1 negatively regulates str-2 expression.  CamKII is a signal converter, transducing an increase in Ca2+ concentration into activation of the nsy-1sek-1–MAPK pathway that determines the fate of Str2 expression in AWC neurons. In the absence of lateral signaling between the AWC neurons, both AWC cells do not express Str2, and this Str2-negative state is probably maintained by the CamKII–MAPK pathway. During normal development, AWC cells communicate with each other, probably through their axons, which contact each other in the nerve ring. This communication inhibits the activity of the CaMKII–MAPK signaling pathway in one of the neurons. The subsequent effects of MAPK on str-2 expression could be through either transcriptional regulation or the direct phosphorylation of target molecules (Ref.4). The C. elegans p38 MAP kinase pathway also control arsenite stress response via regulation of the transcription factor skn-1. C. elegans p38 MAPK pathway composed of sek-1 MAPKK and pmk-1 MAPK regulates arsenite stress response via the transcription factor skn-1. The pmk-1 p38 MAPK pathway is activated by arsenite stress and protects worms from arsenite by functioning in intestine. The skn-1 protein translocates into the nucleus in response to the stress in a manner dependent of the pmk-1 pathway. Then, skn-1 activates transcription of the aip-1 gene encoding a protein carrying the RING finger domain, which is required for protecting cells from arsenite toxicity. Not much information is available for the other two-p38 homologs pmk-2 and pmk-3. Since p38 has been linked to stress responses in mammalian cells, pmk-1, pmk-2, and pmk-3 may form part of a stress-responsive pathway in the intestine of worms. Exposure of worms to heavy metals has been shown to elicit stress responses mainly in the pharynx but also in the intestine. The soil nematode Caenorhabditis elegans is used as a model organism for signal transduction studies, because of the exceptional convenience of genetic manipulation and analysis and the overall cellular simplicity of the animal. It has proved its worth as a model organism in fields such as apoptosis and nervous system development (Ref.5).