ArticleMolecular and cellular biology2007
Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth.
Article in Molecular and cellular biology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 91 citations in OpenAlex.
- Melanoma: Pathogenesis and Targeted Therapy.MedComm · 2026Review
- Impact of protein prenylation inhibition onJournal of bacteriology · 2025Article
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- RalGAP complexes control secretion and primary cilia in pancreatic disease.Life science alliance · 2025Article
- Dissecting the MAPK signaling landscape in malignant melanoma: from BRAF and NRAS mutations to precision combination therapies.Frontiers in cell and developmental biology · 2025Review
- Inhibiting Isoprenylation Suppresses FcεRI-Mediated Mast Cell Function and Allergic Inflammation.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- Regulation of Ras Signaling by S-Nitrosylation.Antioxidants (Basel, Switzerland) · 2023Review
- FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites.Theranostics · 2023Article
- Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma.International journal of molecular sciences · 2022Article
- Review
- Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53.Frontiers in oncology · 2020Review
- SIRT2 and Lysine Fatty Acylation Regulate the Activity of RalB and Cell Migration.ACS chemical biology · 2019Article
- Ral GTPases in Schwann cells promote radial axonal sorting in the peripheral nervous system.The Journal of cell biology · 2019Article
- GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors.Nature communications · 2018Article
- Article
- RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer.Pharmacological reviews · 2018Review
- Ral signaling pathway in health and cancer.Cancer medicine · 2017Review
- Plasma membrane phosphatidylinositol 4-phosphate and 4,5-bisphosphate determine the distribution and function of K-Ras4B but not H-Ras proteins.The Journal of biological chemistry · 2017Article
- RalA is overactivated in medulloblastoma.Journal of neuro-oncology · 2016Article
- Molecular mechanisms linking geranylgeranyl diphosphate synthase to cell survival and proliferation.Molecular membrane biology · 2016Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Geranylgeranyltransferase I inhibitors (GGTIs) are presently undergoing advanced preclinical studies and have been shown to disrupt oncogenic and tumor survival pathways, to inhibit anchorage-dependent and -independent growth, and to induce apoptosis. However, the geranylgeranylated proteins that are targeted by GGTIs to induce these effects are not known. Here we provide evidence that the Ras-like small GTPases RalA and RalB are exclusively geranylgeranylated and that inhibition of their geranylgeranylation mediates, at least in part, the effects of GGTIs on anchorage-dependent and -independent growth and tumor apoptosis. To this end, we have created the corresponding carboxyl-terminal mutants that are exclusively farnesylated and verified that they retain the subcellular localization and signaling activities of the wild-type geranylgeranylated proteins and that Ral GTPases do not undergo alternative prenylation in response to GGTI treatment. By expressing farnesylated, GGTI-resistant RalA and RalB in Cos7 cells and human pancreatic MiaPaCa2 cancer cells followed by GGTI-2417 treatment, we demonstrated that farnesylated RalB, but not RalA, confers resistance to the proapoptotic and anti-anchorage-dependent growth effects of GGTI-2417. Conversely, farnesylated RalA but not RalB expression renders MiaPaCa2 cells less sensitive to inhibition of anchorage-independent growth. Furthermore, farnesylated RalB, but not RalA, inhibits the ability of GGTI-2417 to suppress survivin and induce p27(Kip1) protein levels. We conclude that RalA and RalB are important, functionally distinct targets for GGTI-mediated tumor apoptosis and growth inhibition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.