Dissecting JNK signaling, one KKKinase at a time

Stronach, Beth

doi:10.1002/dvdy.20283

Cited by 67 publications

(76 citation statements)

References 69 publications

(134 reference statements)

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“…alph regulates SAPK signaling under various stress conditions: A number of studies conducted in flies have documented the protective role that JNK signaling plays under stress conditions (Stronach 2005). We sought to determine whether Alph could also modulate JNK signaling in response to stress.…”

Section: Resultsmentioning

confidence: 99%

“…Several MAPKKKs have also been linked to these pathways in flies. They correspond to Slipper (Slpr; MLK homolog), Wallenda (Wnd; DLK/ LZK homolog), Tak1, Tak1-like 1 and 2, Mekk1, and Ask1/Pk92B (Stronach 2005). Mutant alleles were isolated for most of these and genetic evidence not only showed their role in SAPK pathways, but also linked their respective activities to specific developmental events or stress responses.…”

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confidence: 99%

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The PP2C Alphabet Is a Negative Regulator of Stress-Activated Protein Kinase Signaling in Drosophila

et al. 2009

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The Jun N-terminal kinase and p38 pathways, also known as stress-activated protein kinase (SAPK) pathways, are signaling conduits reiteratively used throughout the development and adult life of metazoans where they play central roles in the control of apoptosis, immune function, and environmental stress responses. We recently identified a Drosophila Ser/Thr phosphatase of the PP2C family, named Alphabet (Alph), which acts as a negative regulator of the Ras/ERK pathway. Here we show that Alph also plays an inhibitory role with respect to Drosophila SAPK signaling during development as well as under stress conditions such as oxidative or genotoxic stresses. Epistasis experiments suggest that Alph acts at a step upstream of the MAPKKs Hep and Lic. Consistent with this interpretation, biochemical experiments identify the upstream MAPKKKs Slpr, Tak1, and Wnd as putative substrates. Together with previous findings, this work identifies Alph as a general attenuator of MAPK signaling in Drosophila.

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Section: Resultsmentioning

confidence: 99%

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The PP2C Alphabet Is a Negative Regulator of Stress-Activated Protein Kinase Signaling in Drosophila

et al. 2009

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“…Collectively, these data suggest that RhoGEF2, pbl, Rac1, and Rho1 require JNK activity for their cooperation with Ras ACT , but that east and rib cooperate with Ras ACT independently of JNK. Finally, to determine whether upregulation of JNK signaling was sufficient for cooperation with Ras ACT , we coexpressed Ras ACT (via the ey driver) with various transgenes encoding components of the JNK signaling pathway (Stronach 2005); Bsk ( JNK), Hep ( JNK kinase), Hep ACT (activated version of Hep), Msn ( JNK kinase kinase kinase), and Eiger (tumor necrosis factor, TNF, homolog, which signals through the JNK pathway). We also knocked down a negative regulator of the pathway, the JNK phosphatase, Puc (using UAS-puc RNAi ), in the ey.Ras ACT background.…”

Section: Uas-pbl-gfp#8mentioning

confidence: 99%

Identification of Novel Ras-Cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-Family/JNK Pathway Is a Central Driver of Tumorigenesis

et al. 2011

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We have shown previously that mutations in the apico-basal cell polarity regulators cooperate with oncogenic Ras (Ras ACT ) to promote tumorigenesis in Drosophila melanogaster and mammalian cells. To identify novel genes that cooperate with Ras ACT in tumorigenesis, we carried out a genome-wide screen for genes that when overexpressed throughout the developing Drosophila eye enhance Ras ACT -driven hyperplasia. Ras ACT -cooperating genes identified were Rac1 Rho1, RhoGEF2, pbl, rib, and east, which encode cell morphology regulators. In a clonal setting, which reveals genes conferring a competitive advantage over wildtype cells, only Rac1, an activated allele of Rho1 (Rho1 ACT ), RhoGEF2, and pbl cooperated with Ras ACT , resulting in reduced differentiation and large invasive tumors. Expression of RhoGEF2 or Rac1 with Ras ACT upregulated Jun kinase ( JNK) activity, and JNK upregulation was essential for cooperation. However, in the whole-tissue system, upregulation of JNK alone was not sufficient for cooperation with Ras ACT , while in the clonal setting, JNK upregulation was sufficient for Ras ACT -mediated tumorigenesis. JNK upregulation was also sufficient to confer invasive growth of Ras V12 -expressing mammalian MCF10A breast epithelial cells. Consistent with this, HER2 1 human breast cancers (where human epidermal growth factor 2 is overexpressed and Ras signaling upregulated) show a significant correlation with a signature representing JNK pathway activation. Moreover, our genetic analysis in Drosophila revealed that Rho1 and Rac are important for the cooperation of RhoGEF2 or Pbl overexpression and of mutants in polarity regulators, Dlg and aPKC, with Ras ACT in the whole-tissue context. Collectively our analysis reveals the importance of the RhoGEF/ Rho-family/JNK pathway in cooperative tumorigenesis with Ras ACT .

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“…Genetic analyses in model organisms and biochemical studies in cultured cells have revealed that different JNK-dependent responses require selective use of various MAP3K proteins (Chen et al 2002;Stronach 2005;Cuevas et al 2007;Craig et al 2008;Cronan et al 2012). Figure 7 Tak1-dependent antibacterial defense in the absence or presence of ectopic chimera protein expression.…”

Section: Discussionmentioning

confidence: 99%

Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling inDrosophila

Stronach

Lennox²,

Garlena

2014

Genetics

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A highly diverse set of protein kinases functions as early responders in the mitogen-and stress-activated protein kinase (MAPK/SAPK) signaling pathways. For instance, humans possess 14 MAPK kinase kinases (MAP3Ks) that activate Jun kinase (JNK) signaling downstream. A major challenge is to decipher the selective and redundant functions of these upstream MAP3Ks. Taking advantage of the relative simplicity of Drosophila melanogaster as a model system, we assessed MAP3K signaling specificity in several JNK-dependent processes during development and stress response. Our approach was to generate molecular chimeras between two MAP3K family members, the mixed lineage kinase, Slpr, and the TGF-b activated kinase, Tak1, which share 32% amino acid identity across the kinase domain but otherwise differ in sequence and domain structure, and then test the contributions of various domains for protein localization, complementation of mutants, and activation of signaling. We found that overexpression of the wild-type kinases stimulated JNK signaling in alternate contexts, so cells were capable of responding to both MAP3Ks, but with distinct outcomes. Relative to wild-type, the catalytic domain swaps compensated weakly or not at all, despite having a shared substrate, the JNK kinase Hep. Tak1 C-terminal domain-containing constructs were inhibitory in Tak1 signaling contexts, including tumor necrosis factordependent cell death and innate immune signaling; however, depressing antimicrobial gene expression did not necessarily cause phenotypic susceptibility to infection. These same constructs were neutral in the context of Slpr-dependent developmental signaling, reflecting differential subcellular protein localization and by inference, point of activation. Altogether, our findings suggest that the selective deployment of a particular MAP3K can be attributed in part to its inherent sequence differences, cellular localization, and binding partner availability. P ROTEIN kinases are common transducers of information within cells. Indeed, reversible phosphorylation of substrates, by the opposing activities of kinases and phosphatases, is a major currency in cells forming the basis for information relay in many signaling pathways, ultimately transforming cell behavior in response to a changing environment. Unregulated kinase activity, however, has been implicated in numerous diseases of medical concern, notably cancer. One family in particular, the mitogen-activated protein kinases (MAPKs), composed of ERK, p38, and JNK enzymes, are central to a vast array of cellular and pathological processes

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Dissecting JNK signaling, one KKKinase at a time

Cited by 67 publications

References 69 publications

The PP2C Alphabet Is a Negative Regulator of Stress-Activated Protein Kinase Signaling in Drosophila

The PP2C Alphabet Is a Negative Regulator of Stress-Activated Protein Kinase Signaling in Drosophila

Identification of Novel Ras-Cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-Family/JNK Pathway Is a Central Driver of Tumorigenesis

Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling inDrosophila

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