The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival
Open accessAbstract
We have used mouse embryonic fibroblasts (MEFs) devoid of Ras proteins to illustrate that they are essential for proliferation and migration, but not for survival, at least in these cells. These properties are unique to the Ras subfamily of proteins because ectopic expression of other Ras-like small GTPases, even when constitutively active, could not compensate for the absence of Ras proteins. Only constitutive activation of components of the Raf/Mek/Erk pathway was sufficient to sustain normal proliferation and migration of MEFs devoid of Ras proteins. Activation of the phosphatidylinositol 3-kinase (PI3K)/PTEN/Akt and Ral guanine exchange factor (RalGEF)/Ral pathways, either alone or in combination, failed to induce proliferation or migration of Rasless cells, although they cooperated with Raf/Mek/Erk signalling to reproduce the full response mediated by Ras signalling. In contrast to current hypotheses, Ras signalling did not induce proliferation by inducing expression of D-type Cyclins. Rasless MEFs had normal levels of Cyclin D1/Cdk4 and Cyclin E/Cdk2. However, these complexes were inactive. Inactivation of the pocket proteins or knock down of pRb relieved MEFs from their dependence on Ras signalling to proliferate.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“the ablation of all RAS isoform expression causes death of adult mice within a few weeks of induction (60, 61).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [60]
In the citing paper
“The activated state of KRAS accumulating in vivo results in the activation of downstream signaling pathways and is associated with tumorigenesis, aggressive disease, and poor prognosis [14, 15].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [15]
In the citing paper
“The activated state of KRAS accumulating in vivo results in the activation of downstream signaling pathways and is associated with tumorigenesis, aggressive disease, and poor prognosis [14, 15].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [15]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Marshall, C. J. (1995) · Cell · doi:10.1016/0092-8674(95)90401-8 · Cited by 3,906
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
Engelman, J. A., Luo, J., & Cantley, L. C. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1879 · Cited by 3,330
Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer
Roberts, P. J., & Der, C. J. (2007) · Oncogene · doi:10.1038/sj.onc.1210422 · Cited by 2,788
The ErbB signaling network: receptor heterodimerization in development and cancer
Olayioye, M. A., Neve, R. M., Lane, H. A., & Hynes, N. E. (2000) · The EMBO Journal · doi:10.1093/emboj/19.13.3159 · Cited by 2,489
Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization
Diehl, J. A., Cheng, M., Roussel, M. F., & Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.22.3499 · Cited by 2,130
RAS oncogenes: the first 30 years
Malumbres, M., & Barbacid, M. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1097 · Cited by 1,902 · cited 1×
“These studies have illustrated how Ras proteins become activated by growth factor receptors and have unveiled those pathways implicated in mediating downstream signalling to their ultimate effectors (reviewed in Malumbres and Barbacid, 2003).”
BackgroundSelf-citationBeyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis
Cully, M., You, H., Levine, A. J., & Mak, T. W. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1819 · Cited by 1,267
The RAF proteins take centre stage
Wellbrock, C., Karasarides, M., & Marais, R. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1498 · Cited by 1,223
Rodriguez‐Viciana, P., Warne, P. H., Khwaja, A., Marte, B. M., Pappin, D., Das, P., Waterfield, M. D., Ridley, A. J., & Downward, J. (1997) · Cell · doi:10.1016/s0092-8674(00)80226-3 · Cited by 1,060
Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane
Leevers, S. J., Paterson, H. F., & Marshall, C. J. (1994) · Nature · doi:10.1038/369411a0 · Cited by 1,011
Lin, A. W., Barradas, M., Stone, J. C., van Aelst, L., Serrano, M., & Lowe, S. W. (1998) · Genes & Development · doi:10.1101/gad.12.19.3008 · Cited by 945
Mutant PIK3CA promotes cell growth and invasion of human cancer cells.
Samuels, Y., Diaz, L. A., Schmidt-Kittler, O., Cummins, J. M., DeLong, L., Cheong, I., Rago, C., Huso, D. L., Lengauer, C., Kinzler, K. W., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.014 · Cited by 915
Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells
Mulcahy, L. S., Smith, M. R., & Stacey, D. W. (1985) · Nature · doi:10.1038/313241a0 · Cited by 851
Senescence of human fibroblasts induced by oncogenic Raf
Zhu, J., Woods, D., McMahon, M., & Bishop, J. M. (1998) · Genes & Development · doi:10.1101/gad.12.19.2997 · Cited by 826
Inhibition of NIH 3T3 Cell Proliferation by a Mutant ras Protein with Preferential Affinity for GDP
Feig, L. A., & Cooper, G. M. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.8.3235-3243.1988 · Cited by 799
Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6
Malumbres, M., Sotillo, R., Santamarı́a, D., Galán, J., Cerezo, A., Ortega, S., Dubus, P., & Barbacid, M. (2004) · Cell · doi:10.1016/j.cell.2004.08.002 · Cited by 793
Self-citationActivation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation
Khosravi-Far, R., Solski, P. A., Clark, G. J., Kinch, M. S., & Der, C. J. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.11.6443 · Cited by 683
Defective Thymocyte Maturation in p44 MAP Kinase (Erk 1) Knockout Mice
Pagès, G., Guérin, S., Grall, D., Bonino, F., Smith, A., Anjuere, F., Auberger, P., & Pouysségur, J. (1999) · Science · doi:10.1126/science.286.5443.1374 · Cited by 654
Multiple ras functions can contribute to mammalian cell transformation
White, M. A., Nicolette, C. A., Minden, A., Polverino, A. J., Aelst, L. V., Karin, M., & Wigler, M. H. (1995) · Cell · doi:10.1016/0092-8674(95)90507-3 · Cited by 653
Binding of Ras to Phosphoinositide 3-Kinase p110α Is Required for Ras- Driven Tumorigenesis in Mice
Gupta, S., Ramjaun, A. R., Haiko, P., Wang, Y., Warne, P. H., Nicke, B., Nye, E. L., Stamp, G., Alitalo, K. K., & Downward, J. (2007) · Cell · doi:10.1016/j.cell.2007.03.051 · Cited by 603
Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context
Guerra, C. E., Mijimolle, N., Dhawahir, A., Dubus, P. R., Barradas, M., Serrano, M., Campuzano, V., & Barbacid, M. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00191-0 · Cited by 577
Self-citationK-ras is an essential gene in the mouse with partial functional overlap with N-rasPreprint
Johnson, L., Greenbaum, D. C., Cichowski, K. M., Mercer, K. L., Murphy, E. A., Schmitt, E. S., Bronson, R. T., Umanoff, H., Edelmann, W., Kucherlapati, R., et al. (1997) · Genes & Development · doi:10.1101/gad.11.19.2468 · Cited by 540
Aktaş, H., Cai, H., & Cooper, G. M. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.7.3850 · Cited by 410
RAS and RHO GTPases in G1-phase cell-cycle regulation
Coleman, M. L., Marshall, C. J., & Olson, M. F. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1365 · Cited by 366
K-Ras is essential for the development of the mouse embryo
Koera, K., Nakamura, K. D., Nakao, K., Miyoshi, J., Toyoshima, K., Hatta, T., Otani, H., Aiba, A., & Katsuki, M. (1997) · Oncogene · doi:10.1038/sj.onc.1201284 · Cited by 355
Role of ERas in promoting tumour-like properties in mouse embryonic stem cells
Takahashi, K., Mitsui, K., & Yamanaka, S. (2003) · Nature · doi:10.1038/nature01646 · Cited by 338
The Role of Erk1 and Erk2 in Multiple Stages of T Cell Development
Fischer, A. M., Katayama, C. D., Pagès, G., Pouysségur, J., & Hedrick, S. Μ. (2005) · Immunity · doi:10.1016/j.immuni.2005.08.013 · Cited by 333
Rap1: a key regulator in cell-cell junction formation
Kooistra, M. R. H., Dubé, N., & Bos, J. L. (2006) · Journal of Cell Science · doi:10.1242/jcs.03306 · Cited by 325
Embryonic lethality and fetal liver apoptosis in mice lacking the c‐raf‐1 gene
Mikula, M., Schreiber, M., Husak, Z., Kučerová, L., Rüth, J., Wieser, R., Zatloukal, K., Beug, H., Wagner, E. F., & Baccarini, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.8.1952 · Cited by 311
Robinson, M. J., Stippec, S. A., Goldsmith, E. J., White, M. A., & Cobb, M. H. (1998) · Current Biology · doi:10.1016/s0960-9822(07)00485-x · Cited by 311
Esteban, L. M., Vicario‐Abejón, C., Fernández‐Salguero, P. M., Fernández‐Medarde, A., Swaminathan, N., Yienger, K., Lopez, E., Malumbres, M., McKay, R. D. G., Ward, J. M., et al. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.5.1444-1452.2001 · Cited by 298
Self-citationThe Ras-association domain family (RASSF) members and their role in human tumourigenesis
van der Weyden, L., & Adams, D. J. (2007) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2007.06.003 · Cited by 284
Buday, L., & Downward, J. (2008) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2008.05.001 · Cited by 235
Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27Kip1 and p21Cip1
Martín, A., Odajima, J., Hunt, S. L., Dubus, P. R., Ortega, S., Malumbres, M., & Barbacid, M. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.006 · Cited by 223
Self-citationRodriguez-Viciana, P., Oses-Prieto, J., Burlingame, A., Fried, M., & McCormick, F. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.027 · Cited by 215
Wide spectrum of tumors in knock‐in mice carrying a Cdk4 protein insensitive to INK4 inhibitors
Sotillo, R., Dubus, P., Martn, J., de la Cueva, E., Ortega, S., Malumbres, M., & Barbacid, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.23.6637 · Cited by 208
Self-citationGenetics of RAS signaling in C. elegans
Sternberg, P. W., & Han, M. (1998) · Trends in Genetics · doi:10.1016/s0168-9525(98)01592-3 · Cited by 205
Mek2 Is Dispensable for Mouse Growth and Development
Bélanger, L.-F., Roy, S., Tremblay, M. G., Brott, B. K., Steff, A., Mourad, W. M., Hugo, P., Erikson, R. L., & Charron, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.14.4778-4787.2003 · Cited by 181
Role of Rho-family proteins in cell adhesion and cancer
Malliri, A., & Collard, J. G. (2003) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(03)00098-x · Cited by 176
Stimulation of gene induction and cell growth by the Ras effector Rlf
Wolthuis, R. M. F., de Ruiter, N. D., Cool, R. H., & Bos, J. L. (1997) · The EMBO Journal · doi:10.1093/emboj/16.22.6748 · Cited by 163
Pritchard, C. A., Bolin, L. M., Slattery, R. M., Murray, R. J. S., & McMahon, M. (1996) · Current Biology · doi:10.1016/s0960-9822(02)00548-1 · Cited by 159
Phospholipase C epsilon: linking second messengers and small GTPases
Bunney, T. D., & Katan, M. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.10.007 · Cited by 148
Potenza, N., Vecchione, C., Notte, A., Rienzo, A. D., Rosica, A., Bauer, L., Affuso, A., Felice, M. D., Russo, T., Poulet, R., et al. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400397 · Cited by 126
Ral GTPases: corrupting the exocyst in cancer cells
Camonis, J., & White, M. A. (2005) · Trends in Cell Biology · doi:10.1016/j.tcb.2005.04.002 · Cited by 115
Essential role of B-Raf in ERK activation during extraembryonic development
Galabova‐Kovacs, G., Matzen, D., Piazzolla, D., Meissl, K., Plyushch, T., Chen, A. P., Silva, A. J., & Baccarini, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507399103 · Cited by 113
Plowman, S. J., Williamson, D. J., O’Sullivan, M. J., Doig, J., Ritchie, A., Harrison, D. J., Melton, D. W., Arends, M. J., Hooper, M., & Patek, C. E. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9245-9250.2003 · Cited by 105
Analysis of R-Ras signalling pathways
Self, A. J., Caron, E., Paterson, H. F., & Hall, A. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.7.1357 · Cited by 101
Ras - a versatile cellular switch
Rommel, C., & Hafen, E. (1998) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(98)80111-1 · Cited by 101
Signalling pathways initiated by receptor protein tyrosine kinases in Drosophila
Perrimon, N. (1994) · Current Opinion in Cell Biology · doi:10.1016/0955-0674(94)90145-7 · Cited by 100
Chen, J., Robles, M. T. S., Dyke, T. V., & Symonds, H. (2020) · PubMed Central · doi:10.17615/5yc7-7p13 · Cited by 98
Plasma membrane recruitment of RalGDS is critical for Ras-dependent Ral activation
Matsubara, K., Kishida, S., Matsuura, Y., Kitayama, H., Noda, M., & Kikuchi, A. (1999) · Oncogene · doi:10.1038/sj.onc.1202425 · Cited by 93
Requirement forMap2k1(Mek1) in extra-embryonic ectoderm during placentogenesis
Bissonauth, V., Roy, S., Gravel, M., Guillemette, S., & Charron, J. (2006) · Development · doi:10.1242/dev.02526 · Cited by 81
Coulier, F., Kumar, R., Ernst, M. K., Klein, R., Martín-Zanca, D., & Barbacid, M. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.8.4202-4210.1990 · Cited by 81
Self-citationGrowth regulation by oncogenes--new insights from model organisms.
Prober, D., & Edgar, B. A. (2001) · Current Opinion in Genetics and Development · doi:10.1016/s0959-437x(00)00151-9 · Cited by 77
Compartmentalized signalling: Ras proteins and signalling nanoclusters
Omerović, J., & Prior, I. A. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.06928.x · Cited by 73
RIN1 Is a Breast Tumor Suppressor Gene
Milstein, M., Mooser, C. K., Hu, H., Fejzo, M. S., Slamon, D. J., Goodglick, L., Dry, S., & Colicelli, J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1147 · Cited by 56
Movilla, N., Crespo, P., & Bustelo, X. R. (1999) · Oncogene · doi:10.1038/sj.onc.1202968 · Cited by 54
Mercer, K., Giblett, S. M., Oakden, A., Brown, J., Marais, R., & Pritchard, C. A. (2005) · Oncogene · doi:10.1038/sj.onc.1208707 · Cited by 37
Link, W., Rosado, A., Fominaya, J. M., Thomas, J. E., & Carnero, A. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20479 · Cited by 34
RAS Signalling Is Abnormal in a c- raf1 MEK1 Double Mutant
Bottorff, D. A., Stang, S. L., Agellon, S., & Stone, J. C. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.9.5113 · Cited by 29
Flagged first, then by citations
Cited by
Sorted by citations
RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943
ERK signalling: A master regulator of cell behaviour, life and fate
Lavoie, H., Gagnon, J., & Therrien, M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0255-7 · Cited by 1,185
RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103
A Pericyte Origin of Spinal Cord Scar Tissue
Göritz, C., Dias, D. O., Tomilin, N., Barbacid, M., Shupliakov, O., & Frisén, J. (2011) · Science · doi:10.1126/science.1203165 · Cited by 858
Self-citationDirect small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
Ostrem, J. M. L., & Shokat, K. M. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.139 · Cited by 641
Metadata
- Authors
- Drosten, M., Dhawahir, A., Sum, E. Y. M., Urosevic, J., Lechuga, C. G., Esteban, L. M., Castellano, E., Guerra, C., Santos, E., & Barbacid, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Universidad de Salamanca (ES)
- Corresponding author
- Barbacid, Mariano
- ORCID
- Venue
- The EMBO Journal
- Published
- 2010-02-11
- Volume
- 29
- Issue
- 6
- Pages
- 1091-1104
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2845279
- OpenAlex
- W2113609800
- Cited by
- 347
- References
- 60
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 33 · 2023: 22 · 2022: 35 · 2021: 38 · 2020: 23 · 2019: 13 · 2018: 23 · 2017: 21 · 2016: 11 · 2015: 15 · 2014: 9 · 2013: 17 · 2012: 25
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Ras signaling, Ras proteins, cell proliferation, cell migration, cell survival, mouse embryonic fibroblasts, Raf/MEK/ERK pathway, PI3K/Akt signaling, cyclin D1/CDK4, cyclin E/CDK2, pocket proteins, retinoblastoma protein, cell cycle regulation
- MeSH terms
- Animals, Cell Movement, Cell Survival, Fibroblasts, Signal Transduction, ras Proteins, Phosphatidylinositol 3-Kinases, Extracellular Signal-Regulated MAP Kinases, raf Kinases, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
