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Mpk2: Biological Overview | References

The p38 mitogen-activated protein kinase (MAPK) cascade is an evolutionarily conserved signalling mechanism involved in processes as diverse as apoptosis, cell fate determination, immune function and stress response. Aberrant p38 signalling has been implicated in many human diseases, including heart disease, cancer, arthritis and neurodegenerative diseases. To further understand the role of p38 in these processes, a Drosophila strain was generated that is null for the D-p38a gene. Mutants are homozygous viable and show no observable developmental defects. However, flies lacking D-p38a are susceptible to some environmental stresses, including heat shock, oxidative stress and starvation. These phenotypes only partially overlap those caused by mutations in D-MEKK1 and dTAK1, suggesting that the D-p38a gene is required to mediate some, but not all, of the functions ascribed to p38 signalling (Craig, 2004).

p38/HOG1 was first identified in yeast as a gene required for osmotic maintenance. p38 signalling has since been shown to be important in organisms as diverse as plants and humans, and in processes including apoptosis, cell fate determination, immunity and stress responses. Aberrant p38 signalling has been implicated in many human diseases, including heart disease, cancer, arthritis and neurodegenerative disease, making it an attractive target for pharmaceutical intervention. For this reason, defining the processes regulated by p38 in vivo is essential (Craig, 2004).

The mitogen-activated protein kinase (MAPK) signalling cascade consists of three components: MAPK, MAPK kinase (MAPKK) and MAPKK kinase (MAPKKK). The main families of MAPKs are the extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Like all MAPKs, p38s are serine/threonine kinases, which contain a canonical TGY dual phosphorylation motif (Craig, 2004).

Four vertebrate p38 genes have been identified: α, β, δ and γ. However, the requirements for p38 in development and homeostasis remain the least clearly defined of the MAPKs. Murine p38α knockout mice are embryonic lethal and show defects in angiogenesis. Single gene knockouts for MKK3 and MKK6 are viable and lack developmental defects, whereas the phenotype of double MKK3 and MKK6 knockouts mimics the p38α mutant, making detailed in vivo analysis difficult. Mutations that disrupt p38 pathway signalling in Caenorhabditis elegans result in mild defects in olfactory neuron cell fate determination, sensitivity to high metal ion concentrations and starvation, or pathogen resistance (Craig, 2004).

Two Drosophila p38 MAPK genes, D-p38a and D-p38b, have been identified. D-p38 activity is increased in Drosophila cell lines in response to a variety of environmental stimuli, including osmotic shock, heat shock, oxidative stress, immune stimulation, serum starvation and UV radiation (S. J. Han, 1998; Z. S. Han, 1998). The MAPKKs D-MKK3/licorne and D-MKK4 have been shown to activate both p38 isoforms in vitro (S. J. Han, 1998; Z. S. Han, 1998). A small deletion that removes several genes including D-MKK3/licorne results in embryos with axis determination defects, although interpretation of these data is complicated by the presence of other genes in the deletion. Additionally, the Drosophila genome contains two MAPKKK genes implicated in p38 signalling. Both D-MEKK1 and dTAK1 (TGF-Activated Kinase) mutants have been isolated, and are homozygous viable and fertile, with no observed developmental defects. D-MEKK1 mutants show stress response phenotypes including sensitivity to heat shock and osmotic stress, but have a normal immune response, whereas dTAK1 mutants have a strong immune response deficiency phenotype. Overexpression screens indicate that TGF-β/dTAK1 signalling during development may act through JNK, D-p38a or D-p38b, depending on the overexpression system and tissue used (Adachi-Yamada, 1999; Takatsu, 2000; Mihaly, 2001). The relationship between D-MEKK1 and the p38 kinases is complex (Inoue, 2001); phosphorylation of p38 in response to heat shock and osmotic stress is reduced but not abolished in D-MEKK1 null mutants, indicating that another MAPKKK is also partially responsible for p38 phosphorylation in the stress response (Craig, 2004).

Importantly, no mutations in either Drosophila p38 gene have been reported so far. This paper reportd the phenotypes of a complete deletion of D-p38a. Mutants show only partial phenotypic overlap with D-MEKK1, sharing susceptibility to some environmental stresses but not to others. D-p38a mutants show no detectable developmental defects, suggesting that D-p38a and D-p38b may be partially redundant as mediators of at least some aspects of MAPKK/MAPKKK activity (Craig, 2004).

To address the role of p38 signalling in vivo, a D-p38a null strain, D-p38a¹, was generated using a series of P-element-mediated mutagenesis strategies. The EP(3)3637 P-element (820 base pairs (bp) upstream of the D-p38a locus was mobilized. A new line was recovered that contained a second P-element insertion, EP(3)3637-2, 263 bp downstream of the D-p38a locus. These two elements were then simultaneously excised, creating a complete deletion of the D-p38a locus. The original EP(3)3637 was precisely excised, leaving both flanking genes intact, as determined by direct sequencing. Reverse transcription–PCR (RT–PCR) confirmed that this strain is null for the D-p38a locus (Craig, 2004).

Unlike mouse p38α mutants, which are embryonic lethal (Adams, 2000; Allen, 2000; Tamura, 2000), D-p38a¹ flies are viable and fertile, and show no developmental abnormalities. No gross defects in patterning or apoptosis were observed in developing embryonic or larval tissues, including the embryonic nervous system, or the leg, wing and eye imaginal discs, in contrast to mutants of the Drosophila EGFR/Ras/MAPK and JNK pathways. Expected mendelian ratios of viable progeny were observed from crosses of mutants to flies heterozygous for a chromosomal deficiency of the D-p38a region (48% D-p38a¹/+ versus 52% D-p38a¹/deficiency, n=353). In addition, no interaction was observed when one allele of jnk/bsk¹ or jnk/bsk² was introduced into a D-p38a¹ background; deficiencies removing one copy of D-p38b or both MKK3/lic and MKK7/hep also had no effect. Reducing D-p38b activity by overexpression of a D-p38b antisense construct (Adachi-Yamada, 1999) in a wild-type or D-p38a¹ background similarly resulted in no developmental defects. Loss of one copy of D-p38a suppressed the ommatidial polarity phenotype induced by overexpression of the planar polarity gene disheveled (dsh) (Paricio, 1999); however, removal of both copies of D-p38a¹ failed to modify the hypomorphic phenotype of dsh¹, making the significance of this observation unclear (Craig, 2004).

On the basis of previous work demonstrating the role of p38 signalling in environmental stress responses, the susceptibility of D-p38a mutants to a variety of such stresses was tested. Adult D-p38a¹ mutants showed reduced resistance to dry starvation. In addition, D-p38a¹ mutant flies are susceptible to 37°C heat shock. This susceptibility seems to be a specific defect in the heat-shock response, as the average lifespan of D-p38a¹ flies was unchanged compared with wild type at both 25°C and 29°C. This finding is in contrast to the phenotype observed for adult D-MEKK1 mutant flies, which were largely wild type in their response to heat shock. Lastly, D-p38a¹ mutants are susceptible to oxidative stress; flies placed on medium containing 1% H₂O₂ showed a reduced lifespan compared with both wild-type and D-MEKK1 mutant flies (Craig, 2004).

Curiously, unlike D-MEKK1 mutant flies, D-p38a¹ mutants were not susceptible to osmotic shock. The viability of D-p38a¹ homozygous and heterozygous flies was equivalent when reared on food containing 0.2 M NaCl, whereas the viability of D-MEKK1 homozygous flies was reduced, as previously reported. A smaller reduction was observed in D-MEKK1^ur36 viability than previously reported (Inoue, 2001); the line has been subsequently outcrossed and this disparity in sensitivity to osmotic shock may reflect a difference in the genetic background. Although dTAK1 mutants are immune response deficient, and overexpression of p38a in vivo impaired the innate immune response of larvae (Z. S. Han, 1998), no immune response deficiency was observed in D-p38a¹ mutant adults. Northern analysis showed that following septic injury, the inducible expression of five representative antimicrobial peptide genes, diptericin, attacinA, cecropinA, defensin and drosomycin, was similar in control and mutant flies. Moreover, survival of D-p38a mutants following bacterial infection was not compromised. Additionally, wound healing appeared normal in adults and embryos. Finally, Affymetrix oligonucleotide arrays were used to provide a more global measure of gene regulation after infection. Microarray analysis indicated that antimicrobial peptide gene expression was comparable to controls, as was the expression of other genes important in immune and stress responses: although some variation in expression levels was observed between control and mutant flies, such variation is normal for immune response genes (Craig, 2004).

One potential exception is induction of attacinA, which was consistently reduced on microarrays for D-p38a flies. However, subsequent attempts to confirm this result using RT-PCR and Northern analysis did not clearly confirm this result. There are four attacin genes (attacinA-D) in the Drosophila genome, and cross-hybridization of the attacinA probe to these other genes makes it difficult to determine which (if any) of them is defective in the response to septic injury. Because the viability of the D-p38a flies after septic injury is normal, any defect in the induction of the single attacinA gene may not have a significant effect on the overall immune response of the mutants (Craig, 2004).

To demonstrate that the stress responses are indeed due to loss of D-p38a function, rescue experiments were performed by expressing D-p38a on an inducible ubiquitous heat-shock promoter. Ectopic expression of D-p38a from a single copy of the transgene in a wild-type background did not change survival of 37°C heat shock. However, similar expression of D-p38a in a D-p38a¹ mutant background was successful in rescuing mutant survival to 86.8% of wild-type levels (Craig, 2004).

Surprisingly, a further increase in expression derived from two copies of the transgene in a D-p38a mutant background resulted in a less robust rescue of heat stress, to 75.4% of wild-type levels. In addition, expressing D-p38a with two copies of the transgene in a wild-type background further reduced the survival rate to just 33.6% of control. This suggests that levels of D-p38a above a certain threshold can inhibit the ability of flies to adapt to heat shock. Therefore, although these experiments confirm that signalling through D-p38a mediates heat-shock response, it is also clear that tight regulation of D-p38a is required for appropriate stress response signalling (Craig, 2004).

Thus, genotypically null D-p38a¹ strain lacks defects in development or apoptosis. D-p38a mutants are sensitive to some environmental stresses, such as heat shock, dry starvation and H₂O₂ exposure. D-p38a flies are not sensitive to high osmolarity or infection, distinguishing them from D-MEKK1 and dTAK1 flies, respectively. Another MAPK, such as D-p38b or JNK, may mediate these processes. Significantly, reduction of D-p38b or JNK did not show any additional phenotypes in a D-p38a null background, although the ability of residual D-p38b or JNK to provide full function cannot be ruled out. Conversely, D-p38a mutants are more susceptible to acute heat shock and oxidative stress, whereas D-MEKK1 mutants responded in a manner similar to wild type. This difference suggests that at least for some responses, D-p38a activity is independent of D-MEKK1. These phenotypes highlight the complexity of signalling in this pathway; phosphorylation of p38 in response to heat and osmotic stress is reduced but not abolished in D-MEKK1 mutants, indicating that another MAPKKK may be partially responsible for phosphorylating the p38 MAPKs (Inoue, 2001). To assess the p38 pathway function more completely, mutations in the D-MKK3/licorne, D-MKK4 and D-p38b loci will be required (Craig, 2004).

p38 signalling is a potential target for pharmacological intervention in many inflammatory diseases, including pulmonary disease, Crohn's disease and Alzheimer's disease. Clinical trials are presently underway to study the efficacy of p38 inhibitors in rheumatoid arthritis and asthma, among others. Given the chronic nature of these diseases, understanding the consequences of long-term loss of p38 signalling in vivo may be important in predicting potential negative outcomes in patients. Indeed, in one example, clinical development was abandoned after adverse neurological effects were seen in animal models, although it is unclear whether these effects were specific to the loss of p38 function or another unintended target. This study demonstrates that in vivo loss of D-p38a in Drosophila does not have any developmental consequences or affect longevity, but does confer sensitivity to specific environmental stresses (Craig, 2004).

Drosophila activating transcription factor-2 is involved in stress response via activation by p38, but not c-Jun NH(2)-terminal kinase

Activating transcription factor (ATF)-2 is a member of the ATF/cAMP response element-binding protein family of transcription factors, and its trans-activating capacity is enhanced by stress-activated protein kinases such as c-Jun NH2-terminal kinase (JNK) and p38. However, little is known about the in vivo roles played by ATF-2. This study identified the Drosophila homologue of ATF-2 (dATF-2) consisting of 381 amino acids. In response to UV irradiation and osmotic stress, Drosophila p38 (dp38), but not JNK, phosphorylates dATF-2 and enhances dATF-2-dependent transcription. Consistent with this, injection of dATF-2 double-stranded RNA (dsRNA) into embryos did not induce the dorsal closure defects that are commonly observed in the Drosophila JNK mutant. Furthermore, expression of the dominant-negative dp38 enhanced the aberrant wing phenotype caused by expression of a dominant-negative dATF-2. Similar genetic interactions between dATF-2 and the dMEKK1-dp38 signaling pathway were also observed in the osmotic stress-induced lethality of embryos. Loss of dATF-2 in Drosophila S2 cells by using dsRNA abrogates the induction of 40% of the osmotic stress-induced genes, including multiple immune response-related genes. This indicates that dATF-2 is a major transcriptional factor in stress-induced transcription. Thus, dATF-2 is critical for the p38-mediated stress response (Sano, 2005).

The activating transcription factor/cAMP response element-binding protein (ATF/CREB) family of proteins bears a DNA-binding domain consisting of a cluster of basic amino acids and a leucine zipper that together form the so-called b-ZIP structure. These proteins can form homodimers or heterodimers by binding via their leucine zipper motifs, after which they can bind to the cyclical AMP response element (CRE: 5'-TGACGTCA-3') via their basic region. The two major subgroups of the ATF/CREB family proteins are CREB and ATF-2. The CREB subgroup includes CREB and cAMP response element modulator (CREM), whereas the ATF-2 subgroup contains ATF-2, ATFa (recently also called ATF-7), and CRE-BPa. When the Ser-133 residue of CREB is phosphorylated by cAMP-dependent protein kinase, CREB can bind to the transcriptional coactivator CREB-binding protein (CBP), which greatly stimulates the trans-activating capacity of CREB. The trans-activating capacity of ATF-2, on the other hand, is enhanced by the phosphorylation of its Thr-69 and Thr-71 residue by stress-activated protein kinases (SAPKs) such as c-Jun NH₂-terminal kinase (JNK) and p38. SAPKs are activated by various extracellular stress such as UV, osmotic stress, and inflammatory cytokines. All three members of the ATF-2 subgroup bear the trans-activation domain in their N-terminal region: this domain consists of two subdomains, namely, the N-terminal subdomain containing the well known zinc finger motif and the C-terminal subdomain containing the SAPK phosphorylation sites. The latter subdomain has a highly flexible and disordered structure. Although the coactivator CBP binds to the protein surface of b-ZIP domain of ATF-2, the cofactor that binds to the N-terminal activation domain of ATF-2 remains unknown (Sano, 2005).

The physiological roles played by ATF-2 have been analyzed by using mutant mice. Null Atf-2 mutant mice die shortly after birth and display symptoms of severe respiratory distress and have lungs filled with meconium. In the mutant embryos, hypoxia occurs, which may lead to strong gasping respiration with the consequent aspiration of the amniotic fluid containing meconium. This is due to the impaired development of cytotrophoblast cells in the placenta that in turn is caused by decreased levels of expression of the platelet-derived growth factor receptor alpha. In addition, another Atf-2 mutant mouse, which expresses only a fragment of ATF-2, exhibits lowered postnatal viability and growth, a defect in endochondrial ossification, and reduced numbers of cerebellar Purkinje cells. However, the physiological roles played by the other ATF-2 family proteins remain unknown (Sano, 2005).

In Drosophila, three members of the mitogen-activated protein kinase (MAPK) protein family have been identified: Rolled (Erk homologue), dJNK (JNK homologue, also called Basket), and dp38a and dp38b (p38 homologue). Rolled mediates various receptor tyrosine kinase signals in the process of tracheal elaboration, cell proliferation, mesodermal patterning, R7 photoreceptor cell differentiation, and differentiation of terminal embryonic structures. In contrast, the pathway containing Hemipterous (Hep; MAPK kinase [MAPKK] homologue), dJNK, and Drosophila Jun (dJun) is involved in dorsal closure during embryo development. All mutants of this pathway exhibit the dorsal open phenotype and a decreased level of the expression of Decapentaplegic (Dpp), a secretory ligand belonging to the transforming growth factor (TGF)-β superfamily, in leading edge cells. With regard to the dp38s, they are phosphorylated by various stresses, including UV, lipopolysaccharide (LPS), and osmotic stress. The phenotype resulting from the ectopic expression of the dominant negative (DN) dp38b in the wing imaginal disc indicates that dp38b functions downstream of thickvein (Tkv), a type I receptor of the Dpp ligand, in wing morphogenesis (Sano, 2005).

To determine the in vivo function of ATF-2, the Drosophila ATF-2 homologue (dATF-2) has been identified and characterized. dATF-2 is directly phosphorylated by dp38b but not by dJNK. Moreover, genetic analyses indicated that dATF-2 acts in the dp38 signaling pathway. In addition, DNA array analysis demonstrated that dATF-2 is a major transcriptional activator of osmotic stress-inducible genes (Sano, 2005).

The amino acid sequences of the b-Zip domain and the region containing the p38/JNK phosphorylation sites of mammalian ATF-2 are well conserved in dATF-2. However, dATF-2 lacks the N-terminal zinc finger domain that is conserved in the three members of the mammalian ATF-2 family (ATF-2, CRE-BPa, and ATF-a). The N-terminal zinc finger motif and the adjacent region that contains the p38/JNK phosphorylation sites in the mammalian ATF-2 together act as the transcriptional activation domain. Therefore, the mediators that regulate the transcriptional activation of mammalian ATF-2 and dATF-2 may have different characteristics (Sano, 2005).

Extracellular stress such as UV or osmotic stress induces the dp38-induced phosphorylation of dATF-2 at Thr-59 and Thr-61 and this increases the trans-activation capacity of dATF-2. Although mammalian ATF-2 is well known to be phosphorylated not only by p38 but also by JNK, this study found that dJNK neither directly phosphorylated dATF-2 nor enhanced dATF-2-dependent transcription. Furthermore, transgenic embryos expressing DN-dATF-2 or dATF-2 dsRNA did not clearly reveal the dorsal-open phenotype that is common to the Hep, Bsk, dJun, and dFos mutants. The entire amino acid sequence of JNK1 shares 65% identity with dJNK, and the ~50-amino acid stretch within the N-terminal domain of mammalian ATF-2 that contains the phosphorylation sites is also well conserved in dATF-2 (59% identity). Therefore, it is surprising that dJNK cannot phosphorylate dATF-2, unlike what is observed for mammalian JNK and ATF-2. Furthermore, it was found that although dATF-2 is phosphorylated only by dp38, dJun is phosphorylated by both dp38 and dJun. In contrast, mammalian ATF-2 is phosphorylated by both p38 and JNK, whereas Jun is phosphorylated only by JNK. It is worth noting that ATFa is not phosphorylated by JNK. This may raise the possibility that a regulation mechanism of dATF-2 resembles to that of ATFa, and that an ancestral ATF-2/CRE-BPa gene were derived from a duplicated ATFa-like gene. The relationship between SAPKs and transcription factors in Drosophila and mammals may be useful in understanding how the stress-inducible gene expression system is established during evolution (Sano, 2005).

The GAL4-dATF-2 fusions containing the N-terminal 150 amino acids had a stronger activity than those containing the N-terminal 274 amino acids, indicating that the region between amino acids 150 and 274 has a negative effect on the activation domain of dATF-2. In the case of vertebrate ATF-2, the b-ZIP DBD suppresses the ATF-2 activation domain via intramolecular interaction. This difference may suggest that the mechanism by which the C-terminal region suppresses the activation domain is different between vertebrate ATF-2 and dATF-2. It is interesting whether the region between amino acids 150 and 274 of dATF-2 affects the stability or conformation of dATF-2 protein. Wild-type dATF-2 stimulated the luciferase expression from the CRE-containing promoter under nonstimulated condition. Because the alanine mutants of Thr-59 and Thr-61 dramatically decreased this trans-activating capacity of dATF-2, phosphorylation of these residues seems to be essential for trans-activating capacity of dATF-2. These results suggest the possibility that the Thr-59 and Thr-61 residues are phosphorylated at low levels even under nonstimulated condition. This could be due to the low levels of TNF-α or IL-1 involved in serum. Alternatively, other kinase(s) also may phosphorylate these residues, because vertebrate ATF-2 is activated by Raf-MEK-ERK pathway via phosphorylation of Thr-71 (Sano, 2005).

Using two different assay systems, this study has demonstrated at the genetic level that dATF-2 acts in the dp38 signaling pathway. First, it was shown that expression of DN-dp38b enhances the aberrant wing phenotype caused by DN-dATF-2. It has been reported previously that dp38b acts downstream of the Dpp receptor Tkv, because DN-dp38b expressed in the wing imaginal disc causes a phenotype resemble to the mutant of dpp, a Drosophila homologue of mammalian bone morphogenetic protein/TGF-β/activin superfamily. Therefore, dATF-2 may functions in the Dpp signaling pathway. This may be consistent with the finding that mammalian ATF-2 is phosphorylated by TGF-β signaling via TAK1 and p38, and it then directly binds to the Smad3/4 complex to synergistically activate transcription with Smad3/4. This study also demonstrated that DN-dp38b coexpression enhances the sensitivity of embryos expressing DN-dATF-2 to high osmolarity. Thus, dATF-2 acts in the dp38 signaling pathway, at least in wing pattern formation and the response to osmotic stress. However, no oocyte defects were observed in the transgenic flies expressing DN-dATF-2, although the dp38 MAPK pathway is known to be required during oogenesis for asymmetric egg development. Thus, dATF-2 may function only in some specific events that are regulated by the dp38 signaling pathway (Sano, 2005).

DNA array analysis indicated that ~40% of the genes that are induced by osmotic stress are also regulated by dATF-2, indicating that dATF-2 is a major inducer of osmotic stress-inducible gene expression. These genes encode cell surface and cuticle proteins, transporters, and receptors, and various endopeptidases. It is not surprising that osmotic stress may increase the production of cell surface proteins, including some receptors. In addition, the endopeptidases may be produced because high osmolarity may increase the denaturation of proteins, which must then be degraded by the cell. The dATF-2 target genes also include seven immune response genes, namely, several encoding antimicrobial peptides and one encoding a peptidoglycan recognition protein, which binds to the peptidoglycans of bacterial cell walls and triggers immune responses. LPS has been shown to increase the kinase activity of dp38. Consequently, dp38-phosphorylated dATF-2 may directly induce these immune response-related genes. However, it also has been shown that overexpression of dp38 inhibits the expression of immune response genes. This could be explained by the possibility that dp38 overexpression may inhibit the p38 signaling pathway by activating negative feedback regulatory mechanisms, such as the p38α-induced decrease of MKK6 mRNA stability in mammalian cells. In Drosophila, Gram positive bacteria and fungi predominantly induce the Toll signaling pathway to activate genes such as Drosomycin, whereas Gram negative bacteria activate the Imd pathway to activate genes such as Diptericin. DNA array analysis indicated that both Drosomycin and Diptericin are regulated by dATF-2, which suggests that dATF-2 may be a component of both the Toll and Imd pathways. Further analyses of dATF-2 will most likely enhance understanding of the molecular mechanisms involved in the Drosophila immune system (Sano, 2005).

Search PubMed for articles about Drosophila p38a

Adachi-Yamada, T., et al. (1999). p38 mitogen-activated protein kinase can be involved in transforming growth factor beta superfamily signal transduction in Drosophila wing morphogenesis. Mol. Cell. Biol. 19(3): 2322-9. PubMed citation: 10022918

Adams, R. H., et al. (2000). Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell 6: 109-116. PubMed citation: 10949032

Allen, M., et al. (2000). Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. J. Exp. Med. 191: 859-870. PubMed citation: 10704466

Craig, C. R., Fink, J. L., Yagi, Y., Ip, Y. T. and Cagan, R. L. (2004). A Drosophila p38 orthologue is required for environmental stress responses. EMBO Rep. 5(11): 1058-63. PubMed citation: 15514678

Han, S. J., et al. (1998). Molecular cloning and characterization of a Drosophila p38 mitogen-activated protein kinase. J. Biol. Chem. 273(1): 369-74. PubMed citation: 9417090

Han, Z. S., et al. (1998). A conserved p38 mitogen-activated protein kinase pathway regulates Drosophila immunity gene expression. Mol. Cell. Biol. 18(6): 3527-39. PubMed citation: 9584193

Inoue, H. et al. (2001). A Drosophila MAPKKK, D-MEKK1, mediates stress responses through activation of p38 MAPK. EMBO J 20: 5421-5430. PubMed citation: 11574474

Mihaly, J., et al. (2001). The role of the Drosophila TAK homologue dTAK during development. Mech Dev 102: 67-79. PubMed citation: 11287182

Paricio, N., Feiguin, F., Boutros, M., Eaton, S. and Mlodzik, M. (1999). The Drosophila STE20-like kinase misshapen is required downstream of the Frizzled receptor in planar polarity signaling. EMBO J 18: 4669-4678. PubMed citation: 10469646

Sano, Y., et al. (2005). Drosophila activating transcription factor-2 is involved in stress response via activation by p38, but not c-Jun NH(2)-terminal kinase. Mol. Biol. Cell 16(6): 2934-46. PubMed citation: 15788564

Takatsu, Y. et al. (2000). TAK1 participates in c-Jun N-terminal kinase signaling during Drosophila development. Mol Cell Biol 20: 3015-3026. PubMed citation: 10757786

Tamura, K., et al. (2000). Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell 102: 221-231. PubMed citation: 10943842

date revised: 5 July 2008

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