scholarly journals Ras protein abundance correlates with Ras isoform mutation patterns in cancer.

2021 ◽  
Author(s):  
Fiona E Hood ◽  
Yasmina M Sahraoui ◽  
Rosalind E Jenkins ◽  
Ian A Prior
Keyword(s):  
Rank Order ◽  
Protein Abundance ◽  
Ras Mutation ◽  
Ras Protein ◽  
Activating Mutations ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Large Panel ◽  
Kras Protein ◽  
Ras Isoforms

Activating mutations of Ras genes are often observed in cancer. The protein products of the three Ras genes are almost identical. However, for reasons that remain unclear, KRAS is far more frequently mutated than the other Ras isoforms in cancer and RASopathies. We have quantified HRAS, NRAS, KRAS4A and KRAS4B protein abundance across a large panel of cell lines and healthy tissues. We observe consistent patterns of KRAS>NRAS>>HRAS protein expression in cells that correlate with the rank order of Ras mutation frequencies in cancer. Our data provide support for the model of a sweet-spot of Ras dosage mediating isoform-specific contributions to cancer and development. However, they challenge the notion that rare codons mechanistically underpin the predominance of KRAS mutant cancers. Finally, direct measurement of mutant versus wildtype KRAS protein abundance revealed a frequent imbalance that may suggest additional non-gene duplication mechanisms for optimizing oncogenic Ras dosage.

scholarly journals Drugging all RAS isoforms with one pocket

2020 ◽  
Vol 12 (21) ◽  
pp. 1911-1923 ◽  
Author(s):  
Dirk Kessler ◽  
Andreas Bergner ◽  
Jark Böttcher ◽  
Gerhard Fischer ◽  
Sandra Döbel ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Activating Mutations ◽  
Ras Genes ◽  
Human Cancers ◽  
Ras Isoforms

Activating mutations in the three human RAS genes, KRAS, NRAS and HRAS, are among the most common oncogenic drivers in human cancers. Covalent KRASG12C inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRASG12C-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the ‘on state’ have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.

Mutated RAS and constitutively activated Akt delineate distinct oncogenic pathways, which independently contribute to multiple myeloma cell survival

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1998-2004 ◽  
Author(s):  
Torsten Steinbrunn ◽  
Thorsten Stühmer ◽  
Stefan Gattenlöhner ◽  
Andreas Rosenwald ◽  
Anja Mottok ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Survival ◽  
Myeloma Cell ◽  
Akt Pathway ◽  
Multiple Myeloma Cell ◽  
Activating Mutations ◽  
Oncogenic Ras ◽  
Oncogenic Pathways ◽  
Ras Status ◽  
Ras Isoforms

Abstract We have recently shown that approximately half of primary multiple myeloma (MM) samples display constitutive Akt activity, which disposes them for sensitivity to Akt inhibition. The Akt pathway counts among the signaling conduits for oncogenic RAS and activating mutations of K- and N-RAS frequently occur in MM. We therefore analyzed the relation between RAS mutation and Akt dependency in biopsies and CD138-purified cells from MM patients (n = 65) and the function of oncogenic RAS for MM cell survival in a range of MM cell lines with differing RAS status. Whereas RAS mutations do not predict Akt dependency, oncogenic RAS retains an important role for MM cell survival. Knockdown of either K- or N-RAS strongly decreased the viability of MM cells that harbored the respective oncogenic isoform, whereas ablation of wild-type RAS isoforms had little or no effect. Silencing of oncogenic RAS did not affect the Akt pathway, again indicating lack of a direct link. Combined inhibition of RAS and Akt strongly enhanced MM cell death. These data suggest that oncogenic RAS and Akt may independently contribute to MM cell survival. Targeting of both pathways could provide an attractive therapeutic strategy for patients with oncogenic RAS and dysregulated Akt signaling.

scholarly journals Signaling levels mold the RAS mutation tropism of urethane

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Siqi Li ◽  
Christopher M Counter
Keyword(s):  
Human Cancer ◽  
Driver Mutations ◽  
Normal Cells ◽  
Ras Mutation ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Specific Subset ◽  
Oncogenic Mutations ◽  
Cancer Types ◽  
Oncogenic Stress

RAS genes are commonly mutated in human cancer. Despite many possible mutations, individual cancer types often have a ‘tropism’ towards a specific subset of RAS mutations. As driver mutations, these patterns ostensibly originate from normal cells. High oncogenic RAS activity causes oncogenic stress and different oncogenic mutations can impart different levels of activity, suggesting a relationship between oncoprotein activity and RAS mutation tropism. Here, we show that changing rare codons to common in the murine Kras gene to increase protein expression shifts tumors induced by the carcinogen urethane from arising from canonical Q61 to biochemically less active G12 Kras driver mutations, despite the carcinogen still being biased towards generating Q61 mutations. Conversely, inactivating the tumor suppressor p53 to blunt oncogenic stress partially reversed this effect, restoring Q61 mutations. One interpretation of these findings is that the RAS mutation tropism of urethane arises from selection in normal cells for specific mutations that impart a narrow window of signaling that promotes proliferation without causing oncogenic stress.

Ras and Ras mutations in cancer

2013 ◽  
Vol 8 (7) ◽  
pp. 609-624 ◽  
Author(s):  
Satish Rajasekharan ◽  
Thiagarajan Raman
Keyword(s):  
Cancer Biology ◽  
Mapk Pathway ◽  
Point Mutations ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Ras Protein ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Latent Stage ◽  
Clinical Benefits

AbstractRas 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.

scholarly journals Signaling amplitude molds the Ras mutation tropism of urethane

2021 ◽  
Author(s):  
Siqi Li ◽  
Christopher M. Counter
Keyword(s):  
Transcriptional Analysis ◽  
Driver Mutations ◽  
Oncogenic Signaling ◽  
Normal Cells ◽  
Ras Mutation ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Specific Subset ◽  
Oncogenic Mutations ◽  
Oncogenic Stress

AbstractRAS genes are commonly mutated in cancers yet despite many possible mutations, cancers have a ‘tropism’ towards a specific subset. As driver mutations, these patterns ostensibly originate from normal cells. High oncogenic RAS activity causes oncogenic stress and different oncogenic mutations can impart different levels of activity. Here we show that changing rare codons to common in the murine Kras gene to increase translation shifts tumors induced by the carcinogen urethane from arising from canonical Q61 to biochemically less active G12Kras driver mutations, despite the carcinogen still being biased towards generating Q61 mutations. Loss of p53 to blunt oncogenic stress partially reversed this effect, restoring Q61 mutations. Finally, transcriptional analysis revealed similar signaling amongst tumors driven by different mutations and Kras alleles. These finding suggest that the RAS mutation tropism of urethane is largely product of selection in normal cells for mutations promoting proliferation without causing oncogenic stress.Impact statementThe bias towards specific Kras driver mutations during urethane carcinogenesis appears to arise predominantly from the selection of a narrow window of oncogenic signaling in normal cells.

scholarly journals Ras Isoforms from Lab Benches to Lives—What Are We Missing and How Far Are We?

2021 ◽  
Vol 22 (12) ◽  
pp. 6508
Author(s):  
Arathi Nair ◽  
Katharina F. Kubatzky ◽  
Bhaskar Saha
Keyword(s):  
Protein Isoforms ◽  
Initial Assessment ◽  
Cell Type ◽  
Ras Genes ◽  
Ras Gtpase ◽  
Central Protein ◽  
Preferential Localization ◽  
Functional Map ◽  
Ras Isoforms ◽  
Cellular Organelles

The central protein in the oncogenic circuitry is the Ras GTPase that has been under intense scrutiny for the last four decades. From its discovery as a viral oncogene and its non–oncogenic contribution to crucial cellular functioning, an elaborate genetic, structural, and functional map of Ras is being created for its therapeutic targeting. Despite decades of research, there still exist lacunae in our understanding of Ras. The complexity of the Ras functioning is further exemplified by the fact that the three canonical Ras genes encode for four protein isoforms (H-Ras, K-Ras4A, K-Ras4B, and N-Ras). Contrary to the initial assessment that the H-, K-, and N-Ras isoforms are functionally similar, emerging data are uncovering crucial differences between them. These Ras isoforms exhibit not only cell–type and context-dependent functions but also activator and effector specificities on activation by the same receptor. Preferential localization of H-, K-, and N-Ras in different microdomains of the plasma membrane and cellular organelles like Golgi, endoplasmic reticulum, mitochondria, and endosome adds a new dimension to isoform-specific signaling and diverse functions. Herein, we review isoform-specific properties of Ras GTPase and highlight the importance of considering these towards generating effective isoform-specific therapies in the future.

Induction of neurite formation in PC12 cells by microinjection of proto-oncogenic Ha-ras protein preincubated with guanosine-5'-O-(3-thiotriphosphate)

1987 ◽  
Vol 7 (12) ◽  
pp. 4553-4556
Author(s):  
T Satoh ◽  
S Nakamura ◽  
Y Kaziro
Keyword(s):  
Nerve Growth Factor ◽  
Pc12 Cells ◽  
Morphological Differentiation ◽  
The Other ◽  
P21 Protein ◽  
Ras Protein ◽  
Oncogenic Ras ◽  
Neurite Formation ◽  
Pheochromocytoma Pc12 ◽  
Oncogenic Protein

Rat pheochromocytoma (PC12) cells differentiate to neuronal cells in response to nerve growth factor. It has been shown that microinjection of oncogenic but not proto-oncogenic p21 protein induces morphological differentiation in PC12 cells (D. Bar-Sagi and J. R. Feramisco, Cell 42:841-848, 1985). In this paper we describe a recombinant human proto-oncogenic Ha-ras protein which can effectively induce neurite extension of PC12 cells when microinjected as a complex with guanosine-5'-O-(3-thiotriphosphate). The protein was found to be less effective when complexed with GTP. On the other hand, an oncogenic ras protein coinjected with guanosine-5'-O-(2-thiodiphosphate) was entirely inactive. These results indicate that the binary p21-GTP complex, but not the p21-GDP complex, is effective in inducing differentiation in PC12 cells, irrespective of the oncogenic or the proto-oncogenic protein.

scholarly journals Induction of neurite formation in PC12 cells by microinjection of proto-oncogenic Ha-ras protein preincubated with guanosine-5'-O-(3-thiotriphosphate).

1987 ◽  
Vol 7 (12) ◽  
pp. 4553-4556 ◽  
Author(s):  
T Satoh ◽  
S Nakamura ◽  
Y Kaziro
Keyword(s):  
Nerve Growth Factor ◽  
Pc12 Cells ◽  
Morphological Differentiation ◽  
The Other ◽  
P21 Protein ◽  
Ras Protein ◽  
Oncogenic Ras ◽  
Neurite Formation ◽  
Pheochromocytoma Pc12 ◽  
Oncogenic Protein

Rat pheochromocytoma (PC12) cells differentiate to neuronal cells in response to nerve growth factor. It has been shown that microinjection of oncogenic but not proto-oncogenic p21 protein induces morphological differentiation in PC12 cells (D. Bar-Sagi and J. R. Feramisco, Cell 42:841-848, 1985). In this paper we describe a recombinant human proto-oncogenic Ha-ras protein which can effectively induce neurite extension of PC12 cells when microinjected as a complex with guanosine-5'-O-(3-thiotriphosphate). The protein was found to be less effective when complexed with GTP. On the other hand, an oncogenic ras protein coinjected with guanosine-5'-O-(2-thiodiphosphate) was entirely inactive. These results indicate that the binary p21-GTP complex, but not the p21-GDP complex, is effective in inducing differentiation in PC12 cells, irrespective of the oncogenic or the proto-oncogenic protein.

scholarly journals Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5081
Author(s):  
Yuta Adachi ◽  
Ryo Kimura ◽  
Kentaro Hirade ◽  
Hiromichi Ebi
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Metabolic Reprogramming ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Activating Mutations ◽  
Survival Signaling ◽  
Kras Protein ◽  
Effector Pathways ◽  
Specific Inhibitors

Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.

Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras

1991 ◽  
Vol 11 (8) ◽  
pp. 4053-4064 ◽  
Author(s):  
D W Stacey ◽  
L A Feig ◽  
J B Gibbs
Keyword(s):  
Soluble Form ◽  
Detectable Effect ◽  
Mutant Proteins ◽  
Ras Protein ◽  
Downstream Target ◽  
Oncogenic Ras ◽  
Binding Function ◽  
Transforming Activity ◽  
Nih 3T3 ◽  
Effector Binding

Two dominant inhibitory Ras mutant proteins were analyzed by microinjection. One, [Asn-17]Ras, had a substitution in the putative Mg(2+)-binding site of Ha-Ras. The other, RAST, had a mutation in a yeast RAS protein that impaired its GTPase activity and increased its affinity for GAP. RAST also had a mutation that blocked its localization to the plasma membrane. In NIH 3T3 cells [Asn-17]Ras inhibited the function of normal Ras much more efficiently than that of oncogenic Ras. In contrast, RAST interfered with the transforming activity of oncogenic Ras more efficiently than that of normal Ras. These conclusions were based on two separate types of analysis. The inhibitory Ras mutant proteins were first microinjected into cells stably transformed either by oncogenic Ras or by high levels of expression of cellular Ras. Results obtained in stably transformed cells were then verified by coinjection of the inhibitory Ras mutant proteins together with transforming concentrations of either oncogenic or normal Ras protein. Whereas RAST was active in soluble form. [Asn-17]Ras required membrane localization for activity. Furthermore, mutations in the GAP/effector-binding domain reduced or eliminated the inhibitory activity of RAST but had no detectable effect on [Asn-17]Ras. These results are consistent with the possibility that [Asn-17]Ras functions by blocking the activation of endogenous Ras proteins, while RAST functions by blocking the ability of activated Ras to stimulate a downstream target within the cells. The properties of RAST suggest that interference with the GAP/effector-binding function of RAS represents a strategy for the preferential inactivation of oncogenic Ras in cells.

Sign in / Sign up

Export Citation Format

Share Document