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Science 9 February 1996:
Vol. 271. no. 5250, pp. 810 - 812
DOI: 10.1126/science.271.5250.810
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Reports

Stimulation of Membrane Ruffling and MAP Kinase Activation by Distinct Effectors of RAS

Tom Joneson,  Michael A. White,  Michael H. Wigler,  Dafna Bar-Sagi (1)

The RAS guanine nucleotide binding proteins activate multiple signaling events that regulate cell growth and differentiation. In quiescent fibroblasts, ectopic expression of activated H-RAS (H-RASV12, where V12 indicates valine-12) induces membrane ruffling, mitogen-activated protein (MAP) kinase activation, and stimulation of DNA synthesis. A mutant of activated H-RAS, H-RASV12C40 (where C40 indicates cysteine-40), was identified that was defective for MAP kinase activation and stimulation of DNA synthesis, but retained the ability to induce membrane ruffling. Another mutant of activated H-RAS, H-RASV12S35 (where S35 indicates serine-35), which activates MAP kinase, was defective for stimulation of membrane ruffling and induction of DNA synthesis. Expression of both mutants resulted in a stimulation of DNA synthesis that was comparable to that induced by H-RASV12. These results indicate that membrane ruffling and activation of MAP kinase represent distinct RAS effector pathways and that input from both pathways is required for the mitogenic activity of RAS.


T. Joneson and D. Bar-Sagi, Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
M. A. White and M. H. Wigler, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
(1) To whom correspondence should be addressed.


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Signals from the Ras, Rac, and Rho GTPases Converge on the Pak Protein Kinase in Rat-1 Fibroblasts.
Y. Tang, J. Yu, and J. Field (1999)
Mol. Cell. Biol. 19, 1881-1891
   Abstract »    Full Text »    PDF »
Role of Extracellular Matrix and Ras in Regulation of Glomerular Epithelial Cell Proliferation.
A. V. Cybulsky, A. J. McTavish, J. Papillon, and T. Takano (1999)
Am. J. Pathol. 154, 899-908
   Abstract »    Full Text »    PDF »
Loop 6 of RhoA Confers Specificity for Effector Binding, Stress Fiber Formation, and Cellular Transformation.
H. Zong, N. Raman, L. A. Mickelson-Young, S. J. Atkinson, and L. A. Quilliam (1999)
J. Biol. Chem. 274, 4551-4560
   Abstract »    Full Text »    PDF »
Membrane Interactions of a Constitutively Active GFP-Ki-Ras 4B and Their Role in Signaling. EVIDENCE FROM LATERAL MOBILITY STUDIES.
H. Niv, O. Gutman, Y. I. Henis, and Y. Kloog (1999)
J. Biol. Chem. 274, 1606-1613
   Abstract »    Full Text »    PDF »
Activated MEK Stimulates Expression of AP-1 Components Independently of Phosphatidylinositol 3-Kinase (PI3-Kinase) but Requires a PI3-Kinase Signal To Stimulate DNA Synthesis.
I. Treinies, H. F. Paterson, S. Hooper, R. Wilson, and C. J. Marshall (1999)
Mol. Cell. Biol. 19, 321-329
   Abstract »    Full Text »    PDF »
Early biochemical events in insulin-stimulated fluid phase endocytosis.
D. M. Pitterle, R. T. Sperling, M. G. Myers Jr., M. F. White, and P. J. Blackshear (1999)
Am J Physiol Endocrinol Metab 276, E94-E105
   Abstract »    Full Text »    PDF »
A Function for Phosphatidylinositol 3-Kinase beta  (p85alpha -p110beta ) in Fibroblasts during Mitogenesis: Requirement for Insulin- and Lysophosphatidic Acid-Mediated Signal Transduction.
S. Roche, J. Downward, P. Raynal, and S. A. Courtneidge (1998)
Mol. Cell. Biol. 18, 7119-7129
   Abstract »    Full Text »
Regulation of Exit from Quiescence by p27 and Cyclin D1-CDK4.
M. H. Ladha, K. Y. Lee, T. M. Upton, M. F. Reed, and M. E. Ewen (1998)
Mol. Cell. Biol. 18, 6605-6615
   Abstract »    Full Text »
Regulation of cytoskeletal mechanics and cell growth by myosin light chain phosphorylation.
S. Cai, L. Pestic-Dragovich, M. E. O'Donnell, N. Wang, D. Ingber, E. Elson, and P. De Lanerolle (1998)
Am J Physiol Cell Physiol 275, C1349-C1356
   Abstract »    Full Text »    PDF »
Myoblast city, the Drosophila homolog of DOCK180/CED-5, is required in a Rac signaling pathway utilized for multiple developmental processes.
K. M. Nolan, K. Barrett, Y. Lu, K.-Q. Hu, S. Vincent, and J. Settleman (1998)
Genes & Dev. 12, 3337-3342
   Abstract »    Full Text »
Oncogenic Ha-Ras-dependent Mitogen-activated Protein Kinase Activity Requires Signaling Through the Epidermal Growth Factor Receptor.
M. Hamilton and A. Wolfman (1998)
J. Biol. Chem. 273, 28155-28162
   Abstract »    Full Text »    PDF »
CDO, A Robo-related Cell Surface Protein that Mediates Myogenic Differentiation.
J.-S. Kang, P. J. Mulieri, C. Miller, D. A. Sassoon, and R. S. Krauss (1998)
J. Cell Biol. 143, 403-413
   Abstract »    Full Text »    PDF »
Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling.
A. W. Lin, M. Barradas, J. C. Stone, L. van Aelst, M. Serrano, and S. W. Lowe (1998)
Genes & Dev. 12, 3008-3019
   Abstract »    Full Text »
The Raf-MEK-ERK Cascade Represents a Common Pathway for Alteration of Intracellular Calcium by Ras and Protein Kinase C in Cardiac Myocytes.
P. D. Ho, D. K. Zechner, H. He, W. H. Dillmann, C. C. Glembotski, and P. M. McDonough (1998)
J. Biol. Chem. 273, 21730-21735
   Abstract »    Full Text »    PDF »
Increasing Complexity of the Ras Signaling Pathway.
A. B. Vojtek and C. J. Der (1998)
J. Biol. Chem. 273, 19925-19928
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Phosphoinositide 3-Kinase Induces Scattering and Tubulogenesis in Epithelial Cells through a Novel Pathway.
A. Khwaja, K. Lehmann, B. M. Marte, and J. Downward (1998)
J. Biol. Chem. 273, 18793-18801
   Abstract »    Full Text »    PDF »
Signaling pathways in Ras-mediated tumorigenicity and metastasis.
C. P. Webb, L. Van Aelst, M. H. Wigler, and G. F. Vande Woude (1998)
PNAS 95, 8773-8778
   Abstract »    Full Text »    PDF »
A Rac1 Effector Site Controlling Mitogenesis through Superoxide Production.
T. Joneson and D. Bar-Sagi (1998)
J. Biol. Chem. 273, 17991-17994
   Abstract »    Full Text »    PDF »


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