MAPK Pathway in Drosophila melanogaster
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MAPK Pathway in Drosophila melanogaster

MAPK (Mitogen-Activated Protein Kinase) signal transduction pathways are evolutionarily conserved in eukaryotic cells and transduce signals in response to a variety of extracellular stimuli. Each pathway is composed of three classes of protein kinase: MAPK, MAPKK (MAPK Kinase) and MAPKKK (MAPK Kinase Kinase). MAPK is activated by tyrosine and threonine phosphorylation catalyzed by a family of dual-specificity protein kinase MAPKKs. MAPKK is in turn activated by phosphorylation mediated by MAPKKK. Cascades of MAPKs mediate responses such as cell proliferation, differentiation, and the regulation of metabolic pathways. There are multiple MAPKs in eukaryotes. Three subgroups of the MAPK superfamily have been identified in mammals: ERK (Extracellular signal-Regulated Kinase), JNK (c-Jun N-terminal Kinase) and p38 (or Mpk2). Drosophila melanogaster expresses all three subgroups of MAPKs: Rl (Rolled; ERK homolog), dJNK/ Basket (Drosophila homolog of JNK), and Dp38a and Dp38b (Drosophila homologs of p38). In contrast to the pleiotropic roles of mammalian MAPKs, the known functions of Drosophila MAPKs are somewhat restricted to particular developmental aspects (Ref.1).

Rolled (ERK homolog) is essential to the proper functioning of the Ras signaling pathway. It is required at least three times during development: as the terminal system which mediates responses through the Tor (Torso) receptor, as neurogenic and wing vein pathways mediate responses through the EGFR (Epidermal Growth Factor Receptor), and for the differentiation of photoreceptors, which mediate responses to the Sevenless receptor. In Drosophila, the Torso receptor tyrosine kinase controls a signaling pathway, which is responsible for determining cell fate in the anterior and posterior terminal regions of developing embryos. Although the Torso receptor is expressed uniformly on the surface of the embryo, it is activated only in terminal regions by the localized action of a diffusible ligand. Binding of Torso to its ligand, Tsl (Torso-like) or Trunk, leads to receptor dimerization, activation of the intracellular kinase domain, and autophosphorylation of the receptor on tyrosine residues. Torso has identified two major sites of tyrosine autophosphorylation, which function in the developing embryo as positive and negative effectors that control or modulate the strength of the Torso signal. Phosphorylation of the positive signaling site (pY630) results in the recruitment of the tyrosine phosphatase Csw (Corkscrew)/SHP2, whereas phosphorylation of the negative site (pY918) recruits RasGAP. Once bound, Csw transmits a positive signal by two different mechanisms; it serves as an adaptor protein for DRK (Downstream of receptor kinase) and GRB2/SOS binding, physically linking Torso to Ras activation, and Csw specifically dephosphorylates pY918, thus preventing the negative regulator RasGAP from associating with Torso. The opposing actions of Csw and RasGAP modulate the strength of the Torso signal, contributing to the establishment of precise boundaries for terminal structure development. The binding of both RasGAP and Csw/SHP2 to vertebrate RTKs indicate that this may be a wide spread regulatory mechanism. Ras1 is a docking protein that attaches itself to the cytoplasmic tails of receptors, which in their turn activate downstream targets. The resultant phosphorylation cascade activates Tll (Tailless) and Hkb (Huckebein), two targets of the terminal system (Ref.2). Another signal is responsible for dorsoventral patterning in the egg and embryo of Drosophila. The signal requires the receptor Torpedo (EGFR). It is found in multiple sites and at varying times during development; in signaling processes that determine egg polarity, during early development to determine the identity of cells in the ventral ectoderm, during neurogenesis, in the development of the Malpighian tubules, and during larval stages in the development of the eye and wing. EGFR interacts with three different ligands: Grk (Gurken), Spitz (the principle ligand), and Argos. Two accessory proteins modulate EGFR signaling: Rhomboid and Star. The signaling molecules downstream of EGFR include Shc (the Drosophila homolog of a mammalian oncogene), DRK (an adaptor protein that docks onto Shc bound to EGFR and a homolog of mammalian GRB2), a guanine nucleotide exchange factor (SOS) activated by DRK, and downstream targets like Ras, Raf and Rolled. All these downstream signaling molecules are members of the Ras-Raf-MAPK pathway that amplifies and transmits receptor signals to various parts of the cell. Signals to the cytoskeleton result in changes in cell shape; signals to the nucleus result in gene activation (Ref.3). Another signal, which is responsible for the differentiation of photoreceptors in Drosophila, mediates through the Sevenless receptor. There are eight photoreceptor cells (R1-R8 cells) in each ommatidium (facet) of the Drosophila compound eye. Induction of R7 involves signals from the R8 photoreceptor. The R8 photoreceptor presents on its surface a ligand, BOSS (Bride of Sevenless), which binds and activates Sevenless receptor tyrosine kinase in the R7 precursor. Activation of Sevenless by BOSS results in the phosphorylation of Sevenless and the transduction of the Sevenless signal, through the Ras pathway, into the nucleus. The docking protein DRK binds to phosphorylated Sevenless, and participates in building a protein complex associated with Sevenless that includes the SOS (Son Of Sevenless) and Ras1 proteins. Ras and its target Raf (a serine/threonine kinase) initiate a phosphorylation cascade that transduces and amplifies the Sevenless signal, resulting in activation of pathway targets like Pointed and Yan (Ref.4).

The second MAPK pathway in Drosophila involves the MAPK called dJNK (Jun-N-terminal kinase), also known as Basket. Drosophila JNK is activated by endotoxic LPS (Lipopolysaccharide). Eiger , the first invertebrate TNF (Tumor Necrosis Factor) superfamily ligand, has been shown to be a physiological ligand for the Drosophila JNK pathway. Eiger can initiate cell death by activating the Drosophila JNK pathway. Although this cell death process is blocked by DIAP1 (Drosophila Inhibitor-of-Apoptosis Protein 1, Thread), it does not require Caspase activity. dJNK pathway also involves an additional kinase, Hep (Hemipterous), Drosophila homologs of MKK7, which serves to phosphorylate dJNK. Both proteins are required for dorsal closure, the sealing of the dorsal region of the embryo late in embryonic development. The Hemipterous gene encodes a kinase required for epithelial cell sheet movement. The phosphorylation cascade involving Hep and dJNK terminates in the phosphorylation of dJun, more properly termed JRA(Jun Related Antigen). Both dJNK and dJun are activated in the immune response of the fly. dJNK is closely associated with DSOR1 (Downstream of Ras1), a Drosophila receptor tyrosine kinase homolog of vertebrate TRK kinases, which mediate responses to neurotropins. The activation of dJun by dJNK may lead to increased AP1 (a heterodimer of dFos/FRA and dJun/JRA) transcriptional activity. JRA, and its partner FRA (Fos Related Antigen) are known to target two genes during dorsal closure, Dpp (Decapentaplegic) and Puckered. Dpp may serve to relay signals that trigger cell shape changes, and FRA expression in neighboring cells, while Puckered, a phosphatase, seems to act in a feedback loop. Puckered expression is upregulated by dJun and in turn, Puckered inactivates the JRA activating kinase Basket, whose function is the activation of JRA. A kinase termed Misshapen acts upstream of Basket, in response to cytoskeletal changes, as a signal transducer that leads to the activation of Basket (Ref.5).

Two Drosophila p38 MAPKs, Dp38a and Dp38b, may be involved in insect immunity and in Dpp-regulated wing morphogenesis. Like mammalian p38, Dp38 MAPKs are activated by stress-inducing and inflammatory stimuli, such as UV irradiation, high osmolarity, heat shock, serum starvation, H2O2 and LPS. Several homologs of other distantly related kinases known to function as MAPKKKs have been found in Drosophila. Dpp is a secretory ligand belonging to the TGF-Beta (Transforming Growth Factor-Beta) superfamily, which triggers various morphogenetic processes through interaction with the receptor Tkv (Thick veins). Dp38b action is downstream of Tkv. Alternatively; it is possible that DMEKK1 activates only Dp38a or Dp38b, but not both, in response to environmental stress. DMEKK1 was identified as a protein that specifically interacts with Lic (Licorne), an MKK that is most similar to the mammalian p38 activators MKK3 and MKK6. DMKK3/Lic can phosphorylate the two Drosophila Dp38a and Dp38b proteins. Lic– D-p38 MAPK signaling pathway plays an important role in the patterning of the Drosophila egg. An important concept that emerges from both the mammalian and Drosophila studies is that MAPKKK loss-of-function mutations can cause a very specific loss of a cellular function, even though the downstream MAPKs respond to alternative stimuli. Thus, while multiple MAPKKKs may be capable of stimulating a particular downstream target such as JNK or p38, activation of a given pathway in response to a specific stimulus requires a specific MAPKKK member. This may provide greater selectivity and specificity of the responses to different stimuli. Drosophila is a good model in which to study the role of MAPK pathways in whole organisms, especially since MAPK signaling cascades homologous to their mammalian counterparts have been shown to exist in Drosophila (Ref.6).