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Science 291 (5506): 1055-1058

Copyright © 2001 by the American Association for the Advancement of Science

Notch Inhibition of RAS Signaling Through MAP Kinase Phosphatase LIP-1 During C. elegans Vulval Development

Thomas Berset, Erika Fröhli Hoier, Gopal Battu, Stefano Canevascini, Alex Hajnal*

During Caenorhabditis elegans vulval development, a signal from the anchor cell stimulates the RTK/RAS/MAPK (receptor tyrosine kinase/RAS/mitogen-activated protein kinase) signaling pathway in the closest vulval precursor cell P6.p to induce the primary fate. A lateral signal from P6.p then activates the Notch signaling pathway in the neighboring cells P5.p and P7.p to prevent them from adopting the primary fate and to specify the secondary fate. The MAP kinase phosphatase LIP-1 mediates this lateral inhibition of the primary fate. LIN-12/NOTCH up-regulates lip-1 transcription in P5.p and P7.p where LIP-1 inactivates the MAP kinase to inhibit primary fate specification. LIP-1 thus links the two signaling pathways to generate a pattern.

Division of Cancer Research, Department of Pathology, University of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
*   To whom correspondence should be addressed. E-mail: ahajnal{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Mitosis-meiosis and sperm-oocyte fate decisions are separable regulatory events.
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PNAS 110, 3411-3416
   Abstract »    Full Text »    PDF »
SEL-10/Fbw7-dependent negative feedback regulation of LIN-45/Braf signaling in C. elegans via a conserved phosphodegron.
C. de la Cova and I. Greenwald (2012)
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   Abstract »    Full Text »    PDF »
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EMBO J. 31, 2486-2497
   Abstract »    Full Text »    PDF »
Geometry, epistasis, and developmental patterning.
F. Corson and E. D. Siggia (2012)
PNAS 109, 5568-5575
   Abstract »    Full Text »    PDF »
LIN-39 and the EGFR/RAS/MAPK pathway regulate C. elegans vulval morphogenesis via the VAB-23 zinc finger protein.
M. W. Pellegrino, S. Farooqui, E. Frohli, H. Rehrauer, S. Kaeser-Pebernard, F. Muller, R. B. Gasser, and A. Hajnal (2011)
Development 138, 4649-4660
   Abstract »    Full Text »    PDF »
Molecular Regulation of the Mitosis/Meiosis Decision in Multicellular Organisms.
J. Kimble (2011)
Cold Spring Harb Perspect Biol 3, a002683
   Abstract »    Full Text »    PDF »
The transcription factor FoxB mediates temporal loss of cellular competence for notochord induction in ascidian embryos.
H. Hashimoto, T. Enomoto, G. Kumano, and H. Nishida (2011)
Development 138, 2591-2600
   Abstract »    Full Text »    PDF »
The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery.
N. F. Neel, T. D. Martin, J. K. Stratford, T. P. Zand, D. J. Reiner, and C. J. Der (2011)
Genes & Cancer 2, 275-287
   Abstract »    Full Text »    PDF »
Executing multicellular differentiation: quantitative predictive modelling of C.elegans vulval development.
N. Bonzanni, E. Krepska, K. A. Feenstra, W. Fokkink, T. Kielmann, H. Bal, and J. Heringa (2009)
Bioinformatics 25, 2049-2056
   Abstract »    Full Text »    PDF »
Intraspecific evolution of the intercellular signaling network underlying a robust developmental system.
J. Milloz, F. Duveau, I. Nuez, and M.-A. Felix (2008)
Genes & Dev. 22, 3064-3075
   Abstract »    Full Text »    PDF »
Mammalian NOTCH-1 Activates beta1 Integrins via the Small GTPase R-Ras.
P. S. Hodkinson, Paul. A. Elliott, Y. Lad, B. J. McHugh, A. C. MacKinnon, C. Haslett, and T. Sethi (2007)
J. Biol. Chem. 282, 28991-29001
   Abstract »    Full Text »    PDF »
Computational modeling of Caenorhabditis elegans vulval induction.
X. Sun and P. Hong (2007)
Bioinformatics 23, i499-i507
   Abstract »    Full Text »    PDF »
An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development.
K. Modzelewska, M. G. Elgort, J. Huang, G. Jongeward, A. Lauritzen, C. H. Yoon, P. W. Sternberg, and N. Moghal (2007)
Mol. Cell. Biol. 27, 3695-3707
   Abstract »    Full Text »    PDF »
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K. Kondoh, K. Sunadome, and E. Nishida (2007)
J. Biol. Chem. 282, 3058-3065
   Abstract »    Full Text »    PDF »
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C. B. Walser, G. Battu, E. F. Hoier, and A. Hajnal (2006)
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   Abstract »    Full Text »    PDF »
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E. A. Kritikou, S. Milstein, P.-O. Vidalain, G. Lettre, E. Bogan, K. Doukoumetzidis, P. Gray, T. G. Chappell, M. Vidal, and M. O. Hengartner (2006)
Genes & Dev. 20, 2279-2292
   Abstract »    Full Text »    PDF »
Cell fate-specific regulation of EGF receptor trafficking during Caenorhabditis elegans vulval development.
A. Stetak, E. F. Hoier, A. Croce, G. Cassata, P. P. Di Fiore, and A. Hajnal (2006)
EMBO J. 25, 2347-2357
   Abstract »    Full Text »    PDF »
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M. Gause, J. C. Eissenberg, A. F. MacRae, M. Dorsett, Z. Misulovin, and D. Dorsett (2006)
Mol. Cell. Biol. 26, 2347-2359
   Abstract »    Full Text »    PDF »
Intercellular coupling amplifies fate segregation during Caenorhabditis elegans vulval development.
C. A. Giurumescu, P. W. Sternberg, and A. R. Asthagiri (2006)
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   Abstract »    Full Text »    PDF »
LIP-1 phosphatase controls the extent of germline proliferation in Caenorhabditis elegans.
M.-H. Lee, B. Hook, L. B. Lamont, M. Wickens, and J. Kimble (2006)
EMBO J. 25, 88-96
   Abstract »    Full Text »    PDF »
The Caenorhabditis elegans homologue of the proto-oncogene ect-2 positively regulates RAS signalling during vulval development.
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EMBO Rep. 6, 1169-1175
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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N. Haruki, K. S. Kawaguchi, S. Eichenberger, P. P. Massion, S. Olson, A. Gonzalez, D. P. Carbone, and T. P. Dang (2005)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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R. Ulm, K. Ichimura, T. Mizoguchi, S. C. Peck, T. Zhu, X. Wang, K. Shinozaki, and J. Paszkowski (2002)
EMBO J. 21, 6483-6493
   Abstract »    Full Text »    PDF »
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L. Wu, T. Sun, K. Kobayashi, P. Gao, and J. D. Griffin (2002)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 277, 21723-21729
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Repression of Activator Protein-1-mediated Transcriptional Activation by the Notch-1 Intracellular Domain.
J. Chu, S. Jeffries, J. E. Norton, A. J. Capobianco, and E. H. Bresnick (2002)
J. Biol. Chem. 277, 7587-7597
   Abstract »    Full Text »    PDF »
The nucleus, a site for signal termination by sequestration and inactivation of p42/p44 MAP kinases.
V. Volmat, M. Camps, S. Arkinstall, J. Pouyssegur, and P. Lenormand (2001)
J. Cell Sci. 114, 3433-3443
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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