ArticleOncogene2000
Mitogenic signaling of Ras is regulated by differential interaction with Raf isozymes.
Article in Oncogene, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
23 citing papers in PubMed, 69 citations in OpenAlex.
- From bench to bedside: murine models of inherited and sporadic brain arteriovenous malformations.Angiogenesis · 2025Review
- Discovery of novel naphthalene-based diarylamides as pan-Raf kinase inhibitors with promising anti-melanoma activity: rational design, synthesis, in vitro and in silico screening.Archives of pharmacal research · 2025Article
- Discovery of Raf Family Is a Milestone in Deciphering the Ras-Mediated Intracellular Signaling Pathway.International journal of molecular sciences · 2022Review
- The Role of PDE8 in T Cell Recruitment and Function in Inflammation.Frontiers in cell and developmental biology · 2021Review
- Separase Inhibitor Sepin-1 Inhibits Foxm1 Expression and Breast Cancer Cell Growth.Journal of cancer science & therapy · 2018Article
- Article
- Piconewton-Scale Analysis of Ras-BRaf Signal Transduction with Single-Molecule Force Spectroscopy.Small (Weinheim an der Bergstrasse, Germany) · 2017Article
- Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation.Cell death and differentiation · 2016Article
- Genomic insights into head and neck cancer.Cancers of the head & neck · 2016Article
- The Kinase Activity-deficient Isoform of the Protein Araf Antagonizes Ras/Mitogen-activated Protein Kinase (Ras/MAPK) Signaling in the Zebrafish Embryo.The Journal of biological chemistry · 2015Article
- Integrated RAS signaling defined by parallel NMR detection of effectors and regulators.Nature chemical biology · 2014Article
- Role of Ras/Raf/MEK/ERK signaling in physiological hematopoiesis and leukemia development.Immunologic research · 2011Review
- Raf family kinases: old dogs have learned new tricks.Genes & cancer · 2011Article
- Silencing the expression of Ras family GTPase homologues decreases inflammation and joint destruction in experimental arthritis.The American journal of pathology · 2010Article
- Raf-1 regulates Rho signaling and cell migration.The Journal of cell biology · 2005Article
- JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.Leukemia · 2004Review
- Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis.Journal of carcinogenesis · 2004Article
- Review
- The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia.Leukemia · 2002Review
- P21(Cip1) induced by Raf is associated with increased Cdk4 activity in hematopoietic cells.Oncogene · 2001Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In the mitogenic signaling cascade interaction of Ras with Raf represents a critical step for the regulation of cell growth and differentiation. The major effector of Ras, the serine/threonine kinase Raf exists as three isoforms with different tissue distributions. We demonstrate that transient transfection of oncogenic Ha-Ras leads to a preferential activation of endogenous c-Raf-1 in HEK 293 cells as opposed to A-Raf. In vitro binding studies using purified Ras binding domains of Raf as well as in vivo bindings tests with full length molecules reveals significantly lower binding affinities of A-Raf to Ha-Ras as compared to other Raf isoforms. The Ras-binding interface of c-Raf differs from A-Raf by a conservative Arg to Lys exchange at residue 59 or 22 respectively. Mutational analysis reveals that this residue represents a point of isozyme discrimination: c-Raf-R59K binds Ha-Ras weaker than the wildtype, likewise A-Raf-K22R increases its affinity to Ha-Ras in vivo and in vitro. Differential binding affinities are reflected in downstream signaling. Immunecomplex kinase assays reveal that Ha-Ras mediated Raf activation is decreased for c-Raf-R59K and increased for A-Raf-K22R when compared to the respective wildtype forms. Thus our observations introduce a new level of isoform discrimination in Ras/Raf signaling as a functional consequence of a conservative amino acid exchange in the Ras binding domains.
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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.