Functional specificity of ras isoforms: so similar but so different
- PMID: 21779495
- PMCID: PMC3128637
- DOI: 10.1177/1947601911408081
Functional specificity of ras isoforms: so similar but so different
Abstract
H-ras, N-ras, and K-ras are canonical ras gene family members frequently activated by point mutation in human cancers and coding for 4 different, highly related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B). Their expression is nearly ubiquitous and broadly conserved across eukaryotic species, although there are quantitative and qualitative differences of expression depending on the tissue and/or developmental stage under consideration. Extensive functional studies have determined during the last quarter century that these Ras gene products are critical components of signaling pathways that control eukaryotic cell proliferation, survival, and differentiation. However, because of their homology and frequent coexpression in various cellular contexts, it remained unclear whether the different Ras proteins play specific or overlapping functional roles in physiological and pathological processes. Initially, their high degree of sequence homology and the observation that all Ras isoforms share common sets of downstream effectors and upstream activators suggested that they were mostly redundant functionally. In contrast, the notion of functional specificity for each of the different Ras isoforms is supported at present by an increasing body of experimental observations, including 1) the fact that different ras isoforms are preferentially mutated in specific types of tumors or developmental disorders; 2) the different transforming potential of transfected ras genes in different cell contexts; 3) the distinct sensitivities exhibited by the various Ras family members for modulation by different GAPs or GEFs; 4) the demonstration that different Ras isoforms follow distinct intracellular processing pathways and localize to different membrane microdomains or subcellular compartments; 5) the different phenotypes displayed by genetically modified animal strains for each of the 3 ras loci; and 6) the specific transcriptional networks controlled by each isoform in different cellular settings.
Keywords: Ras; Ras isoforms; canonical Ras; functional specificity; redundancy.
Conflict of interest statement
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Figures
Similar articles
-
CD40 induces selective routing of Ras isoforms to subcellular compartments.J Cell Commun Signal. 2023 Sep;17(3):1009-1021. doi: 10.1007/s12079-023-00747-w. Epub 2023 May 1. J Cell Commun Signal. 2023. PMID: 37126117 Free PMC article.
-
Ras proteins: paradigms for compartmentalised and isoform-specific signalling.Cell Mol Life Sci. 2007 Oct;64(19-20):2575-89. doi: 10.1007/s00018-007-7133-8. Cell Mol Life Sci. 2007. PMID: 17628742 Free PMC article. Review.
-
A New View of Ras Isoforms in Cancers.Cancer Res. 2016 Jan 1;76(1):18-23. doi: 10.1158/0008-5472.CAN-15-1536. Epub 2015 Dec 10. Cancer Res. 2016. PMID: 26659836 Free PMC article. Review.
-
Ras Isoforms from Lab Benches to Lives-What Are We Missing and How Far Are We?Int J Mol Sci. 2021 Jun 17;22(12):6508. doi: 10.3390/ijms22126508. Int J Mol Sci. 2021. PMID: 34204435 Free PMC article. Review.
-
Ras isoforms: signaling specificities in CD40 pathway.Cell Commun Signal. 2020 Jan 6;18(1):3. doi: 10.1186/s12964-019-0497-1. Cell Commun Signal. 2020. PMID: 31906952 Free PMC article.
Cited by
-
Loss of RAB25 Cooperates with Oncogenes in the Transformation of Human Mammary Epithelial Cells (HMECs) to Give Rise to Claudin-Low Tumors.Biomed Res Int. 2024 May 20;2024:8544837. doi: 10.1155/2024/8544837. eCollection 2024. Biomed Res Int. 2024. PMID: 38803515 Free PMC article.
-
Exploring the Relationship Between KRAS, NRAS, and BRAF Mutations and Clinical Characteristics in Iranian Colorectal Cancer Patients.J Gastrointest Cancer. 2024 May 6. doi: 10.1007/s12029-024-01064-0. Online ahead of print. J Gastrointest Cancer. 2024. PMID: 38709419
-
Conserved allosteric perturbation of the GTPase domains by region 1 of Ras hypervariable regions.Biophys J. 2024 Apr 2;123(7):839-846. doi: 10.1016/j.bpj.2024.02.022. Epub 2024 Feb 27. Biophys J. 2024. PMID: 38419331
-
Oncogenic KRAS triggers metabolic reprogramming in pancreatic ductal adenocarcinoma.J Transl Int Med. 2022 Nov 15;11(4):322-329. doi: 10.2478/jtim-2022-0022. eCollection 2023 Dec. J Transl Int Med. 2022. PMID: 38130635 Free PMC article.
-
Ultrasensitive and High-Resolution Protein Spatially Decoding Framework for Tumor Extracellular Vesicles.Adv Sci (Weinh). 2024 Jan;11(3):e2304926. doi: 10.1002/advs.202304926. Epub 2023 Nov 20. Adv Sci (Weinh). 2024. PMID: 37984870 Free PMC article.
References
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous