Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 96 (23): 13259-13263

Copyright © 1999 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / GENETICS

Functional analysis of CNK in RAS signaling

Marc Therrien*, Allan M. Wong, Elaine Kwan, and Gerald M. Rubin{dagger}

Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200

Contributed by Gerald M. Rubin

Accepted for publication September 16, 1999.

Abstract: Connector enhancer of KSR (CNK) is a multidomain protein required for RAS signaling. Its C-terminal portion (CNKC-term) directly binds to RAF. Herein, we show that the N-terminal portion of CNK (CNKN-term) strongly cooperates with RAS, whereas CNKC-term efficiently blocks RAS- and RAF-dependent signaling when overexpressed in the Drosophila eye. Two effector loop mutants of RASV12, S35 and C40, which selectively activate the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase pathways, respectively, do not cooperate with CNK. However, a strong cooperation is observed between CNK and RASV12G37, an effector loop mutant known in mammals to activate specifically the RAL pathway. We have identified two domains in CNKN-term that are critical for cooperation with RAS. Our results suggest that CNK functions in more than one pathway downstream of RAS. CNKc-term seems to regulate RAF, a component of the MAPK pathway, whereas CNKN-term seems to be involved in a MAPK-independent pathway.

Key Words: RAF


* Present address: Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, PQ, Canada H2W 1R7.

{dagger} To whom reprint requests should be addressed. E-mail: gerry{at}fruitfly.berkeley.edu.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The CNK1 scaffold binds cytohesins and promotes insulin pathway signaling.
J. Lim, M. Zhou, T. D. Veenstra, and D. K. Morrison (2010)
Genes & Dev. 24, 1496-1506
   Abstract »    Full Text »    PDF »
Adult and larval photoreceptors use different mechanisms to specify the same Rhodopsin fates.
S. G. Sprecher, F. Pichaud, and C. Desplan (2007)
Genes & Dev. 21, 2182-2195
   Abstract »    Full Text »    PDF »
The novel SAM domain protein Aveugle is required for Raf activation in the Drosophila EGF receptor signaling pathway..
J.-Y. Roignant, S. Hamel, F. Janody, and J. E. Treisman (2006)
Genes & Dev. 20, 795-806
   Abstract »    Full Text »    PDF »
Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway.
Z. Berger, E. K. Ttofi, C. H. Michel, M. Y. Pasco, S. Tenant, D. C. Rubinsztein, and C. J. O'Kane (2005)
Hum. Mol. Genet. 14, 3003-3011
   Abstract »    Full Text »    PDF »
CNK1 Is a Scaffold Protein That Regulates Src-mediated Raf-1 Activation.
A. Ziogas, K. Moelling, and G. Radziwill (2005)
J. Biol. Chem. 280, 24205-24211
   Abstract »    Full Text »    PDF »
The Scaffold Protein CNK1 Interacts with the Tumor Suppressor RASSF1A and Augments RASSF1A-induced Cell Death.
S. Rabizadeh, R. J. Xavier, K. Ishiguro, J. Bernabeortiz, M. Lopez-Ilasaca, A. Khokhlatchev, P. Mollahan, G. P. Pfeifer, J. Avruch, and B. Seed (2004)
J. Biol. Chem. 279, 29247-29254
   Abstract »    Full Text »    PDF »
p53-regulated Transcriptional Program Associated with Genotoxic Stress-induced Apoptosis.
P. S. Kho, Z. Wang, L. Zhuang, Y. Li, J.-L. Chew, H.-H. Ng, E. T. Liu, and Q. Yu (2004)
J. Biol. Chem. 279, 21183-21192
   Abstract »    Full Text »    PDF »
Human CNK1 Acts as a Scaffold Protein, Linking Rho and Ras Signal Transduction Pathways.
A. B. Jaffe, P. Aspenstrom, and A. Hall (2004)
Mol. Cell. Biol. 24, 1736-1746
   Abstract »    Full Text »    PDF »
Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf.
T. M. LANIGAN, A. LIU, Y. Z. HUANG, L. MEI, B. MARGOLIS, and K.-L. GUAN (2003)
FASEB J 17, 2048-2060
   Abstract »    Full Text »    PDF »
Bimodal regulation of RAF by CNK in Drosophila.
M. Douziech, F. Roy, G. Laberge, M. Lefrancois, A.-V. Armengod, and M. Therrien (2003)
EMBO J. 22, 5068-5078
   Abstract »    Full Text »    PDF »
KSR is a scaffold required for activation of the ERK/MAPK module.
F. Roy, G. Laberge, M. Douziech, D. Ferland-McCollough, and M. Therrien (2002)
Genes & Dev. 16, 427-438
   Abstract »    Full Text »    PDF »
The RAS Effector RIN1 Directly Competes with RAF and Is Regulated by 14-3-3 Proteins.
Y. Wang, R. T. Waldron, A. Dhaka, A. Patel, M. M. Riley, E. Rozengurt, and J. Colicelli (2002)
Mol. Cell. Biol. 22, 916-926
   Abstract »    Full Text »    PDF »
Drosophila-Raf Acts to Elaborate Dorsoventral Pattern in the Ectoderm of Developing Embryos.
K. Radke, K. Johnson, R. Guo, A. Davidson, and L. Ambrosio (2001)
Genetics 159, 1031-1044
   Abstract »    Full Text »    PDF »
Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity.
K Halfar, C Rommel, H Stocker, and E Hafen (2001)
Development 128, 1687-1696
   Abstract »    PDF »
A Genetic Screen for Modifiers of a Kinase Suppressor of Ras-Dependent Rough Eye Phenotype in Drosophila.
M. Therrien, D. K. Morrison, A. M. Wong, and G. M. Rubin (2000)
Genetics 156, 1231-1242
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882