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.

α1‐Adrenoceptor activation of PKC‐ε causes heterologous desensitization of thromboxane receptors in the aorta of spontaneously hypertensive rats

“…second messenger requirements (Webb et al, 2000). Different expressions of PKC isoforms between SHR and WKY smooth muscle may explain TP receptor desensitization caused by α1-adrenoceptor activation in the former (Magnusson et al, 1998;Castellano and Santos, 2011;Dalton et al, 2013). The PKC expression was comparable in aortae of 5-week-old WKY and pre-hypertensive SHR (Sankhanava Kundu, 2008), in line with the observation that previous activation of α1-adrenoceptors did not cause desensitization at that young age in the latter.…”

Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

“…As reviewed recently, 17 potential differences in downstream signaling from KRAS, NRAS, and HRAS are only just emerging. 17,42 However, specific data support this suggestion of an NRAS survival signaling pathway.…”

“…BRAF mutations are mutually exclusive to KRAS and/or NRAS mutation in various tumors including melanoma and colorectal cancer, 7,17,18 suggesting each RAS family member provides a similar oncogenic signal to the RAF/MAPK pathway. This is further supported by analysis of the subset of cancers that mutate multiple RAS family members, including acute lymphoblastic leukemia, 19 myeloma, 7,12 and thyroid cancer 20 ; in each of these, mutations in 1 family member (NRAS, HRAS, or KRAS) are mutually exclusive to mutations in the other family members.…”

STAT1 Promotes KRAS Colon Tumor Growth and Susceptibility to Pharmacological Inhibition of Translation Initiation Factor eIF4A

“…Previous work from our group showed that STAT1 inhibits the tumorigenic potency of HRAS G12V-overexpressing MEFs in nude mice (32), an effect that is different from the ability of STAT1 to promote KRAS-mediated colon tumor growth. Such disparities in STAT1 function can be attributed to differences in the functional specificities of HRAS and KRAS proteins in different tissues (33). Another conceivable explanation is variations in the expression of activated RAS proteins given that the antitumor effects of STAT1 in MEFs were associated with HRAS overexpression, whereas the protumorigenic effects of STAT1 in colon tumors are linked to endogenous expression of activated KRAS.…”