CoChat
Sign Up
Cited by 250Protein Kinase Regulation and GTPase SignalingPancreatic and Hepatic Oncology ResearchCellular transport and secretion

Divergent Roles for RalA and RalB in Malignant Growth of Human Pancreatic Carcinoma Cells

Open access
Lim, Kian-Huat, O'Hayer, Kevin, Adam, Stacey J., Kendall, S. DiSean, Campbell, Paul M., Der, Channing J., Counter, Christopher M.·2006·Current Biology
DOI 10.1016/j.cub.2006.10.023
Open this paper in CoChat — free accountOpen PDF

Abstract

Background The Ral guanine nucleotide-exchange factors (RalGEFs) serve as key effectors for Ras oncogene transformation of immortalized human cells. RalGEFs are activators of the highly related RalA and RalB small GTPases, although only the former has been found to promote Ras-mediated growth transformation of human cells. In the present study, we determined whether RalA and RalB also had divergent roles in promoting the aberrant growth of pancreatic cancers, which are characterized by the highest occurrence of Ras mutations. Results We now show that inhibition of RalA but not RalB expression universally reduced the transformed and tumorigenic growth in a panel of ten genetically diverse human pancreatic cancer cell lines. Despite the apparent unimportant role of RalB in tumorigenic growth, it was nevertheless critical for invasion in seven of nine pancreatic cancer cell lines and for metastasis as assessed by tail-vein injection of three different tumorigenic cell lines tested. Moreover, both RalA and RalB were more commonly activated in pancreatic tumor tissue than other Ras effector pathways. Conclusions RalA function is critical to tumor initiation, whereas RalB function is more important for tumor metastasis in the tested cell lines and thus argues for critical, but distinct, roles of Ral proteins during the dynamic progression of Ras-driven pancreatic cancers.

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.2006.10.023

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 tumor growth and metastasis.

    “The Ras-like GTPases RalA and B are important drivers of tumor growth and metastasis1.”

    From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [1]

    The Discussion reports that RalA is critical for tumorigenic growth and that both RalA and RalB contribute to metastatic growth in the pancreatic cancer models studied. It also says RalB was dispensable for tumorigenic growth, so the claim overstates their shared role in tumor growth. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • 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 [1]

    The Results and Discussion (page unavailable) support roles for both RalA and RalB in metastatic growth of pancreatic cancer cells, but distinguish their functions: RalA, not RalB, was required for transformed and tumorigenic growth. The Discussion treats RalB’s role in survival as a possible explanation for its effect on metastasis, not an established finding in these pancreatic cells. This citation is attached to pancreatic cancer, so the other cancer types in the sentence are not assessed here. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Ral promotes anchorage-independence.

    “Ral promotes anchorage-independence1,20, therefore we measured cell growth in soft agar.”

    From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [1]

    The passage labeled Abstract reports that suppressing RalA impaired anchorage-independent growth in nine of ten pancreatic cancer cell lines. It also reports that suppressing RalB did not impair soft-agar growth, so the unqualified claim about Ral is broader than this paper supports. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Reps1, Ralbp1, and RalA are all implicated in a range of physiological and pathological processes.

    “Reps1, Ralbp1, and RalA are all implicated in a range of physiological and pathological processes (10, 61, 62).”

    From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [61]

    The Discussion describes RalA’s role in pancreatic tumor initiation, invasion, and metastasis, supporting its implication in pathological processes. The passages found do not address Reps1 or Ralbp1, so this source does not support the sentence’s claim about all three proteins. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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

Flagged first, then by citations

Research works printed but not linked: 20

  1. [1]1. Klimstra, D.S. ∙ Longnecker, D.S. K-ras mutations in pancreatic ductal proliferative lesions Am. J. Pathol. 1994; 145:1547-1550 PubMed Google Scholar
  2. [2]2. Hruban, R.H. ∙ van Mansfeld, A.D. ∙ Offerhaus, G.J. ... K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization Am. J. Pathol. 1993; 143:545-554 PubMed Google Scholar
  3. [3]3. Shields, J.M. ∙ Pruitt, K. ∙ McFall, A. ... Understanding Ras: ‘It ain't over 'til it's over’ Trends Cell Biol. 2000; 10:147-154 Full Text Full Text (PDF) Scopus (696) PubMed Google Scholar
  4. [4]4. Bos, J.L. ras oncogenes in human cancer: A review Cancer Res. 1989; 49:4682-4689 PubMed Google Scholar
  5. [6]6. Ishimura, N. ∙ Yamasawa, K. ∙ Karim Rumi, M.A. ... BRAF and K-ras gene mutations in human pancreatic cancers Cancer Lett. 2003; 199:169-173 Crossref Scopus (62) PubMed Google Scholar
  6. [7]7. Yip-Schneider, M.T. ∙ Lin, A. ∙ Barnard, D. ... Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression Int. J. Oncol. 1999; 15:271-279 PubMed Google Scholar
  7. [8]8. 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
  8. [9]9. Samuels, Y. ∙ Wang, Z. ∙ Bardelli, A. ... High frequency of mutations of the PIK3CA gene in human cancers Science. 2004; 304:554 Crossref Scopus (3066) PubMed Google Scholar
  9. [10]10. White, M.A. ∙ Vale, T. ∙ Camonis, J.H. ... A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation J. Biol. Chem. 1996; 271:16439-16442 Crossref Scopus (218) PubMed Google Scholar
  10. [11]11. Hamad, N.M. ∙ Elconin, J.H. ∙ Karnoub, A.E. ... Distinct requirements for Ras oncogenesis in human versus mouse cells Genes Dev. 2002; 16:2045-2057 Crossref Scopus (353) PubMed Google Scholar
  11. [12]12. Rangarajan, A. ∙ Hong, S.J. ∙ Gifford, A. ... Species- and cell type-specific requirements for cellular transformation Cancer Cell. 2004; 6:171-183 Full Text Full Text (PDF) Scopus (452) PubMed Google Scholar
  12. [13]13. Chardin, P. ∙ Tavitian, A. Coding sequences of human ralA and ralB cDNAs Nucleic Acids Res. 1989; 17:4380 Crossref Scopus (72) PubMed Google Scholar
  13. [14]14. 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
  14. [15]15. 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
  15. [16]16. 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
  16. [17]17. Rosse, 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
  17. [18]18. Brummelkamp, T.R. ∙ Bernards, R. ∙ Agami, R. Stable suppression of tumorigenicity by virus-mediated RNA interference Cancer Cell. 2002; 2:243-247 Full Text Full Text (PDF) Scopus (1045) PubMed Google Scholar
  18. [19]19. Lim, K.H. ∙ Counter, C.M. Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance Cancer Cell. 2005; 8:381-392 Full Text Full Text (PDF) Scopus (157) PubMed Google Scholar
  19. [20]20. Chen, W.H. ∙ Horoszewicz, J.S. ∙ Leong, S.S. ... Human pancreatic adenocarcinoma: In vitro and in vivo morphology of a new tumor line established from ascites In Vitro. 1982; 18:24-34 Crossref Scopus (157) PubMed Google Scholar
  20. [21]21. Norman, J. ∙ Franz, M. ∙ Schiro, R. ... Functional glucocorticoid receptor modulates pancreatic carcinoma growth through an autocrine loop J. Surg. Res. 1994; 57:33-38

Cited by

Sorted by citations

Authors
Lim, K.-H., O'Hayer, K., Adam, S. J., Kendall, S. D., Campbell, P. M., Der, C. J., & Counter, C. M.
Affiliations
  • Duke University (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
  • Der, Channing J.
  • Counter, Christopher M.
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2006-12
Volume
16
Issue
24
Pages
2385-2394
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2006.10.023
OpenAlex
W2136940817
Cited by
250
References
2
Citations by year
2026: 2 · 2025: 5 · 2024: 5 · 2023: 14 · 2022: 11 · 2021: 15 · 2020: 10 · 2019: 13 · 2018: 10 · 2017: 9 · 2016: 17 · 2015: 19 · 2014: 18 · 2013: 17 · 2012: 14
FWCI
4.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • U.S. Department of Defense
  • National Institutes of Health (5r01ca042978-30, CA42978)
  • National Cancer Institute (CA42978, CA94184, R01CA094184)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
RalA, RalB, pancreatic cancer, oncogenic Ras, metastasis, tumor invasion, small GTPases, Ras effector pathways, tumor progression
MeSH terms
Adenocarcinoma, Animals, Cell Transformation, Neoplastic, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Transplantation, Pancreatic Neoplasms, Transplantation, Heterologous, ral GTP-Binding Proteins, Cell Line, Tumor, 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