CoChat
Sign Up
Cited by 82Protein Kinase Regulation and GTPase SignalingCellular transport and secretionDevelopmental Biology and Gene Regulation

Genetic Deletion of RALA and RALB Small GTPases Reveals Redundant Functions in Development and Tumorigenesis

Open access
Peschard, Pascal, McCarthy, Afshan, Leblanc-Dominguez, Valérie, Yeo, Maggie, Guichard, Sabrina, Stamp, Gordon, Marshall, Christopher J.·2012·Current Biology
DOI 10.1016/j.cub.2012.09.013
Open this paper in CoChat — free accountOpen PDF

Abstract

RAL small GTPases, encoded by the Rala and Ralb genes, are members of the RAS superfamily of small GTPases and can act as downstream effectors of RAS [1]. Although highly similar, distinct functions have been identified for RALA and RALB: RALA has been implicated in epithelial cell polarity [2], insulin secretion [3], GLUT4 translocation [4, 5], neurite branching, and neuronal polarity [6, 7], and RALB in tumor cell survival [8], migration/invasion [9-12], TBK1 activation [13], and autophagy [14]. To investigate RAL GTPases in vivo, we generated null and conditional knockout mice. Ralb null mice are viable with no overt phenotype; the Rala null leads to exencephaly and embryonic lethality. The exencephaly phenotype is exacerbated in Rala(-/-);Ralb(+/-) embryos; embryos null for Rala and Ralb do not live past gastrulation. Using a Kras-driven non-small cell lung carcinoma mouse model, we found that either RALA or RALB is sufficient for tumor growth. However, deletion of both Ral genes blocks tumor formation. Either RALA or RALB is sufficient for cell proliferation, but cells lacking both fail to proliferate. These studies demonstrate functions of RAL proteins in development, tumorigenesis, and cell proliferation and show that RALA and RALB act in a redundant fashion.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.cub.2012.09.013

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • RalA and RalB are important drivers of the proliferation, survival and metastasis of multiple human cancers including skin, lung, pancreatic, colon, prostate, and bladder.

    “RalA and RalB are important drivers of the proliferation, survival and metastasis of multiple human cancers including skin11, lung12, pancreatic1, colon13, prostate14, and bladder15,16.”

    From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [12]

    The Results and Discussion (page unavailable) reports RNAi studies in human pancreatic cancer cell models suggesting that RALA is required for proliferation and RALB for survival and migration. This supports the pancreatic-cancer portion of the citation, but the paper does not establish metastasis in pancreatic cancer; it describes migration and invasion instead. Its pancreatic mouse-model observation also found that deleting either gene alone did not impair tumor formation. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Genetically engineered mouse models revealed substantial redundancy for Ral proteins in tumorigenesis.

    “genetically engineered mouse models revealed substantial redundancy for Ral proteins in tumorigenesis12.”

    From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [12]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Part of this paper’s reference list could not be split into single entries.

Flagged first, then by citations

Research works printed but not linked: 31

  1. [1]1. Bodemann, B.O. ∙ White, M.A. Ral GTPases and cancer: linchpin support of the tumorigenic platform Nat. Rev. Cancer. 2008; 8:133-140 Crossref Scopus (198) PubMed Google Scholar
  2. [2]2. Shipitsin, M. ∙ Feig, L.A. RalA but not RalB enhances polarized delivery of membrane proteins to the basolateral surface of epithelial cells Mol. Cell. Biol. 2004; 24:5746-5756 Crossref Scopus (113) PubMed Google Scholar
  3. [3]3. Lopez, J.A. ∙ Kwan, E.P. ∙ Xie, L. ... The RalA GTPase is a central regulator of insulin exocytosis from pancreatic islet beta cells J. Biol. Chem. 2008; 283:17939-17945 Crossref Scopus (33) PubMed Google Scholar
  4. [4]4. Chen, X.W. ∙ Leto, D. ∙ Chiang, S.H. ... Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c Dev. Cell. 2007; 13:391-404 Full Text Full Text (PDF) Scopus (169) PubMed Google Scholar
  5. [5]5. Chen, X.W. ∙ Leto, D. ∙ Xiong, T. ... A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action Mol. Biol. Cell. 2011; 22:141-152 Crossref Scopus (80) PubMed Google Scholar
  6. [6]6. Lalli, G. RalA and the exocyst complex influence neuronal polarity through PAR-3 and aPKC J. Cell Sci. 2009; 122:1499-1506 Crossref Scopus (60) PubMed Google Scholar
  7. [7]7. Lalli, G. ∙ Hall, A. Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex J. Cell Biol. 2005; 171:857-869 Crossref Scopus (87) PubMed Google Scholar
  8. [8]8. Chien, Y. ∙ White, M.A. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival EMBO Rep. 2003; 4:800-806 Crossref Scopus (162) PubMed Google Scholar
  9. [9]9. Lim, K.H. ∙ O’Hayer, K. ∙ Adam, S.J. ... Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells Curr. Biol. 2006; 16:2385-2394 Full Text Full Text (PDF) Scopus (196) PubMed Google Scholar
  10. [10]10. Oxford, G. ∙ Owens, C.R. ∙ Titus, B.J. ... RalA and RalB: antagonistic relatives in cancer cell migration Cancer Res. 2005; 65:7111-7120 Crossref Scopus (110) PubMed Google Scholar
  11. [11]11. Rossé, C. ∙ Hatzoglou, A. ∙ Parrini, M.C. ... RalB mobilizes the exocyst to drive cell migration Mol. Cell. Biol. 2006; 26:727-734 Crossref Scopus (116) PubMed Google Scholar
  12. [12]12. Wang, H. ∙ Owens, C. ∙ Chandra, N. ... Phosphorylation of RalB is important for bladder cancer cell growth and metastasis Cancer Res. 2010; 70:8760-8769 Crossref Scopus (46) PubMed Google Scholar
  13. [13]13. Chien, Y. ∙ Kim, S. ∙ Bumeister, R. ... RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival Cell. 2006; 127:157-170 Full Text Full Text (PDF) Scopus (310) PubMed Google Scholar
  14. [14]14. Bodemann, B.O. ∙ Orvedahl, A. ∙ Cheng, T. ... RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly Cell. 2011; 144:253-267 Full Text Full Text (PDF) Scopus (253) PubMed Google Scholar
  15. [15]15. Copp, A.J. ∙ Greene, N.D. ∙ Murdoch, J.N. The genetic basis of mammalian neurulation Nat. Rev. Genet. 2003; 4:784-793 Crossref Scopus (568) PubMed Google Scholar
  16. [16]16. He, W. ∙ Barak, Y. ∙ Hevener, A. ... Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle Proc. Natl. Acad. Sci. USA. 2003; 100:15712-15717 Crossref Scopus (835) PubMed Google Scholar
  17. [17]17. Jackson, E.L. ∙ Willis, N. ∙ Mercer, K. ... Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras Genes Dev. 2001; 15:3243-3248 Crossref Scopus (1540) PubMed Google Scholar
  18. [18]18. Jackson, E.L. ∙ Olive, K.P. ∙ Tuveson, D.A. ... The differential effects of mutant p53 alleles on advanced murine lung cancer Cancer Res. 2005; 65:10280-10288 Crossref Scopus (446) PubMed Google Scholar
  19. [19]19. DuPage, M. ∙ Dooley, A.L. ∙ Jacks, T. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase Nat. Protoc. 2009; 4:1064-1072 Crossref Scopus (641) PubMed Google Scholar
  20. [20]20. Balmain, A. ∙ Pragnell, I.B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene Nature. 1983; 303:72-74 Crossref Scopus (352) PubMed Google Scholar
  21. [21]21. Derksen, P.W. ∙ Liu, X. ∙ Saridin, F. ... Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis Cancer Cell. 2006; 10:437-449 Full Text Full Text (PDF) Scopus (481) PubMed Google Scholar
  22. [22]22. Lim, K.H. ∙ Baines, A.T. ∙ Fiordalisi, J.J. ... Activation of RalA is critical for Ras-induced tumorigenesis of human cells Cancer Cell. 2005; 7:533-545 Full Text Full Text (PDF) Scopus (302) PubMed Google Scholar
  23. [23]23. Lim, K.H. ∙ Brady, D.C. ∙ Kashatus, D.F. ... Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA Mol. Cell. Biol. 2010; 30:508-523 Crossref Scopus (99) PubMed Google Scholar
  24. [24]24. Neel, N.F. ∙ Rossman, K.L. ∙ Martin, T.D. ... The RalB small GTPase mediates formation of invadopodia through a GTPase-activating protein-independent function of the RalBP1/RLIP76 effector Mol. Cell. Biol. 2012; 32:1374-1386 Crossref Scopus (48) PubMed Google Scholar
  25. [25]25. van Dam, T.J. ∙ Bos, J.L. ∙ Snel, B. Evolution of the Ras-like small GTPases and their regulators Small GTPases. 2011; 2:4-16 Crossref Scopus (51) PubMed Google Scholar
  26. [26]26. Zhao, Z. ∙ Rivkees, S.A. Tissue-specific expression of GTPas RalA and RalB during embryogenesis and regulation by epithelial-mesenchymal interaction Mech. Dev. 2000; 97:201-204 Crossref Scopus (13) PubMed Google Scholar
  27. [27]27. Cascone, I. ∙ Selimoglu, R. ∙ Ozdemir, C. ... Distinct roles of RalA and RalB in the progression of cytokinesis are supported by distinct RalGEFs EMBO J. 2008; 27:2375-2387 Crossref Scopus (97) PubMed Google Scholar
  28. [29]29. Male, H. ∙ Patel, V. ∙ Jacob, M.A. ... Inhibition of RalA signaling pathway in treatment of non-small cell lung cancer Lung Cancer. 2012; 77:252-259 Full Text Full Text (PDF) Scopus (33) PubMed Google Scholar
  29. [30]30. Hoch, R.V. ∙ Soriano, P. Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development Development. 2006; 133:663-673 Crossref Scopus (102) PubMed Google Scholar
  30. [32]32. Jonkers, J. ∙ Meuwissen, R. ∙ van der Gulden, H. ... Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer Nat. Genet. 2001; 29:418-425 Crossref Scopus (853) PubMed Google Scholar
  31. [33]33. González-García, A. ∙ Pritchard, C.A. ∙ Paterson, H.F. ... RalGDS is required for tumor formation in a model of skin carcinogenesis Cancer Cell. 2005; 7:219-226 Full Text Full Text (PDF) Scopus (144) PubMed Google Scholar

Cited by

Sorted by citations

Authors
Peschard, P., McCarthy, A., Leblanc-Dominguez, V., Yeo, M., Guichard, S., Stamp, G., & Marshall, C. J.
Affiliations
  • Institute of Cancer Research (GB)
  • Royal Marsden NHS Foundation Trust (GB)
Corresponding author
Marshall, Christopher J.
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2012-11
Volume
22
Issue
21
Pages
2063-2068
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2012.09.013
OpenAlex
W1980704197
Cited by
82
References
2
Citations by year
2026: 4 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 9 · 2018: 4 · 2017: 8 · 2016: 10 · 2015: 4 · 2014: 12 · 2013: 8 · 2012: 1
FWCI
3.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cancer Research UK
  • Terry Fox Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
RalA, RalB, Ras superfamily, gene redundancy, exencephaly, embryonic lethality, tumor growth, non-small cell lung cancer, KRAS-driven tumors, cell proliferation, conditional knockout mice, carcinogenesis, development (biology)
MeSH terms
Animals, Carcinoma, Non-Small-Cell Lung, Cell Transformation, Neoplastic, Cells, Cultured, Lung Neoplasms, Mice, Inbred C57BL, Neural Tube Defects, Signal Transduction, Oncogene Protein p21(ras), Cell Polarity, Mice, Knockout, ral GTP-Binding Proteins, Embryonic Development, Cell Proliferation, Mice, Neural Tube

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