A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways

Brunner, Damian; Oellers, Nadja; Szabad, János; Biggs, William H.; Zipursky, S. Lawrence; Hafen, Ernst

doi:10.1016/0092-8674(94)90362-x

Cited by 403 publications

(304 citation statements)

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“…Sequential activation of the same linear cascade appears to function in other signal transduction pathways. For example, genetic evidence in the Drosophila sevenless pathway indicates that defects in the growth factor receptor can be compensated for by a gain-of-function mutation in MAP kinase (Brunner et al, 1994). These data provide strong support for the view that sequential activation of this linear signal transduction pathway is both necessary and sufficient to produce complex cellular responses.…”

Section: Introductionmentioning

confidence: 74%

Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Thorburn

Carlson

Mansour

et al. 1995

MBoC

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Signaling via the Ras pathway involves sequential activation of Ras, Raf-1, mitogenactivated protein kinase kinase (MKK), and the extracellular signal-regulated (ERK) group of mitogen-activated protein (MAP) kinases. Expression from the c-Fos, atrial natriuretic factor (ANF), and myosin light chain-2 (MLC-2) promoters during phenylephrine-induced cardiac muscle cell hypertrophy requires activation of this pathway. Furthermore, constitutively active Ras or Raf-1 can mimic the action of phenylephrine in inducing expression from these promoters. In this study, we tested whether constitutively active MKK, the molecule immediately downstream of Raf, was sufficient to induce expression. Expression of constitutively active MKK induced ERK2 kinase activity and caused expression from the c-Fos promoter, but did not significantly activate expression of reporter genes under the control of either the ANF or MLC-2 promoters. Expression of CL100, a phosphatase that inactivates ERKs, prevented expression from all of the promoters. Taken together, these data suggest that ERK activation is required for expression from the Fos, ANF, and MLC-2 promoters but MKK and ERK activation is sufficient for expression only from the Fos promoter. Constitutively active MKK synergized with phenylephrine to increase expression from a c-Fos-or an APi-driven reporter. However, active MKK inhibited phenylephrine-and Raf-1-induced expression from the ANF and MLC-2 promoters. A DNA sequence in the MLC-2 promoter that is a target for inhibition by active MKK, but not CL100, was mapped to a previously characterized DNA element (HF1) that is responsible for cardiac specificity. Thus, activation of cardiac gene expression during phenylephrine-induced hypertrophy requires ERK activation but constitutive activation by MKK can inhibit expression by targeting a DNA element that controls the cardiac specificity of gene expression.

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Section: Introductionmentioning

confidence: 74%

Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Thorburn

Carlson

Mansour

et al. 1995

MBoC

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“…In avian cells there is an homologue of c-raf termed c-mil (Jansen et al, 1984;Koenen et al, 1988). Raf proteins are necessary for vulval development in Caenorhabditis elegans (Georgi et al, 1990;Han et al, 1993), R7 photoreceptor formation in Drosophila melanogaster (Perrimon and Desplan, 1994;Brunner et al, 1994;Wassarman et al, 1996) and mesoderm induction in Xenopus laevis (MacNicol et al, 1995;Xu et al, 1996). Transgenic chimeric c-Raf-de®cient mice show growth retardation (Naumann et al, 1997) and B-Raf-de®cient mice die in utero and display defects in endothelial cell di erentiation and survival (Wojnowski et al, 1997).…”

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confidence: 99%

Strict regulation of c-Raf kinase levels is required for early organogenesis of the vertebrate inner ear

et al. 1999

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Regulation of organogenesis involves a dynamic balance of the mechanisms regulating cell division, di erentiation and death. Here we have investigated the pattern of expression of c-Raf kinase in the inner ear during early developmental stages and the consequences of manipulating c-Raf levels by misexpression of c-raf viral vectors in organotypic cultures of otic vesicle explants. We found that otic vesicles expressed c-Raf and its level remained constant during embryonic days 2 and 3 (E2-E3). c-Raf activity was increased in response to insulin like growth factor-I (IGF-I) and the activation by IGF-I of the c-Raf kinase pathway was a requirement to turn on cell proliferation in the otic vesicle. Overexpression of c-raf in E2.5 explants increased the proliferative response to low serum and IGF-I and blocked di erentiation induced by retinoic acid. The increase in c-Raf levels also prevented nerve growth factor (NGF)-dependent induction of programmed cell death. Consistent with these results, the expression of a dominant negative c-Raf mutant potentiated retinoic acid action and decreased the rate of cell proliferation. We conclude that a strict control of c-Raf levels is essential for the co-ordination of the biological processes that operate simultaneously during early inner ear development.

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“…PKA has been shown to be essential for aggregation, cell-type-specific expression of the ecmB gene, the induction of prespore cell differentiation, and the induction of sporulation and spore cell-specific gene expression (1, 27, 35, 36, 40, 56-58, 76, 77 (8, 21-23, 61, 79, 84). In metazoans, both G protein-and tyrosine kinase-coupled receptors regulate growth responses, gene expression, and cellular differentiation via MAPK-containing pathways (2,7,11,51,60,64,83). MAPK family members have also been shown to directly phosphorylate transcription factors in mammalian cells, including Myc, Elk, and Jun proteins, leading to an increase in the rate of transcription (14,29,38,46,59,74,75).…”

mentioning

confidence: 99%

Identification and functional analysis of a developmentally regulated extracellular signal-regulated kinase gene in Dictyostelium discoideum.

Gaskins¹,

Maeda²,

Firtel³

1994

Mol. Cell. Biol.

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We have cloned a developmentally regulated mitogen-activated protein kinase (extracellular signal-regulated kinase) from Dictyostelium discoideum designated ERK1. Using anti-pTyr antibodies, we show that ERKI is phosphorylated on tyrosine in vivo and that it will phosphorylate myelin basic protein. The (16,26). As the aggregate forms, extracellular signals produced within the organism induce cell type differentiation and regulate morphogenesis. These events lead to the production of a migrating slug followed by culmination and the generation of a mature fruiting body containing spores and stalk cells (49,50,80). Biochemical and molecular genetic analyses over the last few years have identified components required for various aspects of these processes and have led to a further understanding of the regulatory pathways controlling development. Genes encoding membrane receptors, coupled GP and Got subunits, the effectors adenylyl cyclase and phospholipase C, and the transcription factor GBF have been cloned and analyzed at a molecular level (12,17,32,65,72,81,82 the membrane to those in the nucleus is cAMP-dependent protein kinase (PKA). PKA has been shown to be essential for aggregation, cell-type-specific expression of the ecmB gene, the induction of prespore cell differentiation, and the induction of sporulation and spore cell-specific gene expression (1, 27, 35, 36, 40, 56-58, 76, 77 (8, 21-23, 61, 79, 84). In metazoans, both G protein-and tyrosine kinase-coupled receptors regulate growth responses, gene expression, and cellular differentiation via MAPK-containing pathways (2,7,11,51,60,64,83). MAPK family members have also been shown to directly phosphorylate transcription factors in mammalian cells, including Myc, Elk, and Jun proteins, leading to an increase in the rate of transcription (14,29,38,46,59,74,75).

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A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways

Cited by 403 publications

References 53 publications

Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Strict regulation of c-Raf kinase levels is required for early organogenesis of the vertebrate inner ear

Identification and functional analysis of a developmentally regulated extracellular signal-regulated kinase gene in Dictyostelium discoideum.

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