Increasing complexity of Ras signaling
Abstract
The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to define a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was defined and conserved in worms, flies and man. This was a remarkable achievement in our efforts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identification of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular effectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple effectors.
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RAS proteins function as binary molecular switches controlling intracellular signaling networks and regulating proliferation, differentiation, and survival.
“RAS proteins function as binary molecular switches that control intracellular signaling networks and regulate proliferation, differentiation, and survival functions (Figure 1) [4].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [4]
In colorectal cancer, mutations in the RAS family, mostly KRAS and NRAS, lock RAS proteins in an active GTP-bound state, constitutively activating MAPK and PI3K independent of external growth signals.
“These mutations lock RAS proteins in an active GTP-bound state, constitutively activating pathways such as MAPK and PI3K, independent of external growth signals [4].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [4]
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- Authors
- Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J., & Der, C. J.
- Affiliations
- Massachusetts Institute of Technology (US)
- National Institutes of Health (US)
- University of North Carolina at Chapel Hill (US)
- Venue
- Oncogene
- Published
- 1998-09-17
- Volume
- 17
- Issue
- 11
- Pages
- 1395-1413
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1993163893
- Cited by
- 1,079
- References
- 0
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 13 · 2023: 11 · 2022: 9 · 2021: 10 · 2020: 12 · 2019: 14 · 2018: 14 · 2017: 12 · 2016: 24 · 2015: 25 · 2014: 29 · 2013: 28 · 2012: 31
- FWCI
- 27.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r01ca055008-03, 5r01ca042978-30, 5r01ca052072-05)
- National Cancer Institute (CA42978, CA 55008, CA52072)
- 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 › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Ras signaling, signal transduction, MAPK signaling, signaling crosstalk, feedback loops, branch points, nuclear transcription factors, oncogenic Ras, cancer
- MeSH terms
- Amino Acid Sequence, Animals, Extracellular Matrix, Humans, Molecular Sequence Data, Neoplasms, Genes, ras, Signal Transduction, Calcium-Calmodulin-Dependent Protein Kinases, Proto-Oncogene Proteins c-raf
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