BRAF V600E Mutation in Multiple Primary Malignancies: A Hairy Affair

White, Richard; Otaibi, Zachary; Rao, Rohit; Finley, Gene Grant

doi:10.7759/cureus.3600

Cited by 5 publications

(5 citation statements)

References 14 publications

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“…This interplay between stability and activity is also observed in other types of signaling proteins. For example, protein kinases are activated by mutations that destabilize them and thereby break regulatory mechanisms, as seen for the V600E cancer mutation in B-Raf (White et al, 2018). The action of the chaperone HSP90 protects the destabilized kinases from unfolding and subsequent proteasomal degradation, allowing the mutant kinases to promote hyperactivation (Taipale et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

A Saturation-Mutagenesis Analysis of the Interplay Between Stability and Activation in Ras

Hidalgo

Nocka

Shah

et al. 2022

Preprint

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Cancer mutations in Ras occur predominantly at three hotspots: Gly 12, Gly 13, and Gln 61. Previously, we reported that deep mutagenesis of H?Ras using a bacterial assay identified many other activating mutations (Bandaru et al., 2017). We now show that the results of saturation mutagenesis of H?Ras in mammalian Ba/F3 cells correlate well with results of bacterial experiments in which H-Ras or K-Ras are co-expressed with a GTPase?activating protein (GAP). The prominent cancer hotspots are not dominant in the Ba/F3 data. We used the bacterial system to mutagenize Ras constructs of different stabilities and discovered a feature that distinguishes the cancer hotspots. While mutations at the cancer hotspots activate Ras regardless of construct stability, mutations at lower-frequency sites (e.g., at Val 14 or Asp 119) can be activating or deleterious, depending on the stability of the Ras construct. We characterized the dynamics of three non-hotspot activating Ras mutants by using NMR to monitor hydrogen?deuterium exchange (HDX). These mutations result in global increases in HDX rates, consistent with the destabilization of Ras. An explanation for these observations is that mutations that destabilize Ras increase nucleotide dissociation rates, enabling activation by spontaneous nucleotide exchange. A further stability decrease can lead to insufficient levels of folded Ras – and subsequent loss of function. In contrast, the cancer hotspot mutations are mechanism-based activators of Ras that interfere directly with the action of GAPs. Our results demonstrate the importance of GAP surveillance and protein stability in determining the sensitivity of Ras to mutational activation.

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Section: Resultsmentioning

confidence: 99%

A Saturation-Mutagenesis Analysis of the Interplay Between Stability and Activation in Ras

Hidalgo

Nocka

Shah

et al. 2022

Preprint

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show abstract

Section: Discussionmentioning

confidence: 99%

A saturation-mutagenesis analysis of the interplay between stability and activation in Ras

Hidalgo

Nocka

Shah

et al. 2022

eLife

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Cancer mutations in Ras occur predominantly at three hotspots: Gly 12, Gly 13, and Gln 61. Previously, we reported that deep mutagenesis of H-Ras using a bacterial assay identified many other activating mutations (Bandaru et al., 2017). We now show that the results of saturation mutagenesis of H-Ras in mammalian Ba/F3 cells correlate well with the results of bacterial experiments in which H-Ras or K-Ras are co-expressed with a GTPase-activating protein (GAP). The prominent cancer hotspots are not dominant in the Ba/F3 data. We used the bacterial system to mutagenize Ras constructs of different stabilities and discovered a feature that distinguishes the cancer hotspots. While mutations at the cancer hotspots activate Ras regardless of construct stability, mutations at lower-frequency sites (e.g. at Val 14 or Asp 119) can be activating or deleterious, depending on the stability of the Ras construct. We characterized the dynamics of three non-hotspot activating Ras mutants by using NMR to monitor hydrogen-deuterium exchange (HDX). These mutations result in global increases in HDX rates, consistent with destabilization of Ras. An explanation for these observations is that mutations that destabilize Ras increase nucleotide dissociation rates, enabling activation by spontaneous nucleotide exchange. A further stability decrease can lead to insufficient levels of folded Ras – and subsequent loss of function. In contrast, the cancer hotspot mutations are mechanism-based activators of Ras that interfere directly with the action of GAPs. Our results demonstrate the importance of GAP surveillance and protein stability in determining the sensitivity of Ras to mutational activation.

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“…The substitution of valine (V) by glutamate (E) at position 600 of the B-Raf protein, accounts for approximately 90% of all BRAF mutations and is designated as V600E [ 44 ]. BRAF V600E mutations were identified in a number of different malignancies, including melanoma, as well as serous ovarian and colorectal cancers [ 45 ].…”

Section: The Interplay Of Braf V600e and Snail-1 In Thyroid Cancermentioning

confidence: 99%

The Role of Snail-1 in Thyroid Cancer—What We Know So Far

Wieczorek-Szukała

Lewiński

2021

JCM

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Thyroid carcinomas, despite the usually indolent behaviour and relatively good overall prognosis, show a high tendency to gain invasive phenotype and metastasise in some cases. However, due to a relatively slow progression, the exact mechanisms governing the metastatic process of thyroid carcinomas, including the epithelial-to-mesenchymal transition (EMT), are poorly described. One of the best-known regulators of cancer invasiveness is Snail-1—a zinc-finger transcription factor that plays a key role as an EMT inducer. More and more attention is being paid to the role of Snail with regard to thyroid cancer development. Apart from the obvious implications in the EMT process, Snail-1 plays an important role in the regulation of chemoresistance of the thyroid cells and cancer stem cell (CSC) formation, and it also interacts with miRNA specific to the thyroid gland. The aim of this review was to summarise the knowledge on Snail-1, especially in the context of thyroid oncogenesis.

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BRAF V600E Mutation in Multiple Primary Malignancies: A Hairy Affair

Cited by 5 publications

References 14 publications

A Saturation-Mutagenesis Analysis of the Interplay Between Stability and Activation in Ras

A Saturation-Mutagenesis Analysis of the Interplay Between Stability and Activation in Ras

A saturation-mutagenesis analysis of the interplay between stability and activation in Ras

The Role of Snail-1 in Thyroid Cancer—What We Know So Far

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