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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Campbell, S., Khosravi-Far, R., Rossman, K. et al. Increasing complexity of Ras signaling. Oncogene 17, 1395–1413 (1998). https://doi.org/10.1038/sj.onc.1202174
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1202174
Keywords
This article is cited by
-
Comprehensive Analysis for Predicting Prognoses and Immune Responses of m6A-Related lncRNAs in Women with Lung Adenocarcinoma
Biochemical Genetics (2023)
-
Monocyte Chemoattractant Protein-1 promotes cancer cell migration via c-Raf/MAPK/AP-1 pathway and MMP-9 production in osteosarcoma
Journal of Experimental & Clinical Cancer Research (2020)
-
RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis—an updated review
Cell Death & Disease (2019)
-
Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation
Nature Communications (2019)
-
Design, synthesis, and biological evaluation of Cyclobentinib (CB1107) as a potential anti-CML agent
Medicinal Chemistry Research (2018)