The role of wild type RAS isoforms in cancer (original) (raw)
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Ras and Ras mutations in cancer
Central European Journal of Biology, 2013
Ras genes are pre-eminent genes that are frequently linked with cancer biology. The functional loss of ras protein caused by various point mutations within the gene, is established as a prognostic factor for the genesis of a constitutively active Ras-MAPK pathway leading to cancer. Ras signaling circuit follows a complex pathway, which connects many signaling molecules and cells. Several strategies have come up for targeting mutant ras proteins for cancer therapy, however, the clinical benefits remain insignificant. Targeting the Ras-MAPK pathway is extremely complicated due its intricate networks involving several upstream and downstream regulators. Blocking oncogenic Ras is still in latent stage and requires alternative approaches to screen the genes involved in Ras transformation. Understanding the mechanism of Ras induced tumorigenesis in diverse cancers and signaling networks will open a path for drug development and other therapeutic approaches.
Mutations affecting the three isoforms of the RAS gene -KRAS, HRAS and NRASrepresent the most common oncogenic event in several cancer types. RAS mutations lead to constitutive activation of the corresponding protein and contribute to different hallmarks of cancers, including increased proliferation and resistance to apoptosis. Activating mutations in KRAS are currently used in the clinic to exclude colorectal cancer patients from treatment with ineffective epidermal growth factor receptor targeted-based therapies. Future studies are needed to fully elucidate the role of all RAS oncogenic variants in cancer biology, as well as to assess the potential prognostic and predictive value of individual RAS genetic alterations in clinical settings other than colorectal cancer.
A New View of Ras Isoforms in Cancers
Cancer research, 2016
Does small GTPase K-Ras4A have a single state or two states, one resembling K-Ras4B and the other N-Ras? A recent study of K-Ras4A made the remarkable observation that even in the absence of the palmitoyl, K-Ras4A can be active at the plasma membrane. Importantly, this suggests that K-Ras4A may exist in two distinct signaling states. In state 1, K-Ras4A is only farnesylated, like K-Ras4B; in state 2, farnesylated and palmitoylated, like N-Ras. The K-Ras4A hypervariable region sequence is positively charged, in between K-Ras4B and N-Ras. Taken together, this raises the possibility that the farnesylated but nonpalmitoylated state 1, like K-Ras4B, binds calmodulin and is associated with colorectal and other adenocarcinomas like lung cancer and pancreatic ductal adenocarcinoma. On the other hand, state 2 may be associated with melanoma and other cancers where N-Ras is a major contributor, such as acute myeloid leukemia. Importantly, H-Ras has two, singly and doubly, palmitoylated states...
A Comprehensive Survey of Ras Mutations in Cancer
Cancer Research, 2012
All mammalian cells express three closely related Ras proteins: H-Ras, K-Ras and N-Ras that promote oncogenesis when mutationally activated at codons 12, 13 or 61. Despite a high degree of similarity between the isoforms, K-Ras mutations are far more frequently observed in cancer and each isoform displays preferential coupling to particular cancer types. We have examined the mutation spectra of Ras isoforms curated from large-scale tumour profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino acid substitution biases. These were unexpected given that these mutations occur in regions that share 100% amino acid sequence identity between the three isoforms. Importantly, many of the mutational biases were not due to differences in exposure to mutagens because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms together with isoform-specific differences in protein structure and signalling that may promote these distinct mutation patterns and differential coupling to specific cancers.
Ras isoform abundance and signalling in human cancer cell lines
Oncogene, 2008
The ubiquitously expressed major Ras isoforms: H-, Kand N-Ras, are highly conserved, yet exhibit different biological outputs. We have compared the relative efficiencies with which epidermal or hepatocyte growth factor activates Ras isoforms and the requirement for specific isoforms in the activation of downstream pathways. We find that the relative coupling efficiencies to each Ras isoform are conserved between stimuli. Furthermore, in both cases, inhibition of receptor endocytosis led to reduced N-and H-Ras activation, but K-Ras was unaffected. Acute knockdown of each isoform with siRNA allows endogenous Ras isoform function and abundance to be probed. This revealed that there is significant variation in the contribution of individual isoforms to total Ras across a panel of cancer cell lines although typically KXNbH. Intriguingly, cancer cell lines where a significant fraction of endogenous Ras is oncogenically mutated showed attenuated activation of canonical Ras effector pathways. We profiled the contribution of each Ras isoform to the total Ras pool allowing interpretation of the effect of isoform-specific knockdown on signalling outcomes. In contrast to previous studies indicating preferential coupling of isoforms to Raf and PtdIns-3kinase pathways, we find that endogenous Ras isoforms show no specific coupling to these major Ras pathways.
Cancer Targets in the Ras Pathway
Cold Spring Harbor Symposia on Quantitative Biology, 2005
Ras proteins play a direct causal role in human cancer and in other diseases. Mutant H-Ras, N-Ras, and K-Ras occur in varying frequencies in different tumor types, for reasons that are not known. Other members of the Ras superfamily may also contribute to cancer. Mutations also occur in downstream pathways, notably B-Raf, PTEN, and PI 3´ kinase: These pathways interact at multiple points, including cyclin D1, and act synergistically. In some cases mutations in Ras and effectors are mutually exclusive; in other cases, they coexist. Drugs blocking elements of the pathway are in different stages of clinical development. One of these, the Raf kinase/VEGF-R2 inhibitor Sorafenib, has already been approved for treatment of renal cancer and is being tested in other indications. However, therapeutic targets in the Ras pathway have not yet been fully validated as bona fide targets.
Targeting RAS signalling pathways in cancer therapy
Nature Reviews Cancer, 2003
RAS proteins: diversity and processing. The RAS proteins are members of a large superfamily of lowmolecular-weight GTP-binding proteins, which can be divided into several families according to the degree of sequence conservation. Different families are important for different cellular processes -the RAS family controls cell growth and the RHO family controls the actin cytoskeleton. Three members of the RAS family -HRAS, KRAS and NRAS -are found to be activated by mutation in human tumours 6 . These three members are very closely related, having 85% amino acid sequence identity and, although they function in very similar ways, some indications of subtle differences between them have recently come to light. The HRAS, KRAS and NRAS proteins are widely expressed, with KRAS being expressed in almost all cell types. Knockout studies have shown that Hras and Nras, either alone or in combination, are not required for normal development in the mouse, whereas Kras is essential 7 . This might reflect different molecular functions of the three proteins, but is more likely to reflect the more ubiquitous expression of KRAS.
Cancer informatics, 2017
The 3 human RAS genes play pivotal roles regulating proliferation, differentiation, and survival in normal cells and become mutated in 15% to 20% of all human tumors and amplified in many others. In this report, we examined data from The Cancer Genome Atlas to investigate the relationship between RAS gene mutational status and messenger RNA expression. We show that all 3 RAS genes exhibit increased expression when they are mutated in a context-dependent manner. In the case of KRAS, this increase is manifested by a larger proportional increase in KRAS4A than KRAS4B, although both increase significantly. In addition, the mutational status of RAS genes can be associated with expression changes in other RAS genes, with most of these cases showing decreased expression. The mutational status associations with expression are recapitulated in cancer cell lines. Increases in expression are mediated by both copy number variation and contextual differences, including mutational status of epide...
Oncogenic Ras Isoforms Signaling Specificity at the Membrane
Cancer research, 2018
How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. There are two major pathways in oncogenic Ras-driven proliferation: MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. All membrane-anchored, proximally located, oncogenic Ras isoforms can promote Raf dimerization and fully activate MAPK signaling. So why the differential statistics of oncogenic isoforms in distinct cancers and what makes KRas so highly oncogenic? Many cell-specific factor...
Significance of Ras Signaling in Cancer and Strategies for its Control
Oncology & Hematology Review (US), 2015
Ras is a GTP-binding protein and is the most widely studied oncoprotein. To achieve its biological activity, it must undergo post-translation modification. Ras acts as a typical molecular switch. The GTP-bound Ras can activate several downstream effector pathways. Ras signaling regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc. Several studies have found mutation in Ras or its effectors in various types of tumors. Therefore, Ras or its downstream effectors can be attractive drug targets against various types of tumors in cancer therapeutics. Some therapeutic agents against Ras effectors, such as Raf, MEK1/2, PI3K, AKT etc., have successfully managed to enter into phase I and II trials. This targeted drug design could be envisaged in mainly four ways, such as prevention of Ras-GTP formation, covalent locking of the GDP-bound Ras, inhibition of Ras-effector interactions, or impairment of post-translational modificati...