The effects of mutant Ras proteins on the cell signalome

Takács, Tamás; Kudlik, Gyöngyi; Kurilla, Anita; Szeder, Bálint; Buday, László; Vas, Virag

doi:10.1007/s10555-020-09912-8

Cited by 45 publications

(31 citation statements)

References 126 publications

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“…When looking at DEGs between Negative RL and RAS/PAX8-PPARg positive samples, the main difference was the pronounced expression of genes in PI3K/AKT pathway. In cancer, the common drivers for this pathway are activating mutations in PIK3CA gene, inactivating modifications in PTEN, and activating modifications in AKT isoforms or in PI3K activating receptor tyrosine kinases (RTKs) [78]. We found mutations in RTK genes ERBB2 (also known as HER2) and FLT4 (also known as VEGFR-3) and cytokine receptor OSMR in negative RL samples that have been previously described as able to activate the PI3K/AKT pathway [78,79].…”

Section: Discussionmentioning

confidence: 74%

Molecular Signature Expands the Landscape of Driver Negative Thyroid Cancers

Bim

Carneiro

Buzatto

et al. 2021

Cancers

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Thyroid cancer is the most common endocrine malignancy. However, the cytological diagnosis of follicular thyroid carcinoma (FTC), Hürthle cell carcinoma (HCC), and follicular variant of papillary thyroid carcinoma (FVPTC) and their benign counterparts is a challenge for preoperative diagnosis. Nearly 20–30% of biopsied thyroid nodules are classified as having indeterminate risk of malignancy and incur costs to the health care system. Based on that, 120 patients were screened for the main driver mutations previously described in thyroid cancer. Subsequently, 14 mutation-negative cases that are the main source of diagnostic errors (FTC, HCC, or FVPTC) underwent RNA-Sequencing analysis. Somatic variants in candidate driver genes (ECD, NUP98,LRP1B, NCOR1, ATM, SOS1, and SPOP) and fusions were described. NCOR1 and SPOP variants underwent validation. Moreover, expression profiling of driver-negative samples was compared to 16 BRAF V600E, RAS, or PAX8-PPARg positive samples. Negative samples were separated in two clusters, following the expression pattern of the RAS/PAX8-PPARg or BRAF V600E positive samples. Both negative groups showed distinct BRS, ERK, and TDS scores, tumor mutation burden, signaling pathways and immune cell profile. Altogether, here we report novel gene variants and describe cancer-related pathways that might impact preoperative diagnosis and provide insights into thyroid tumor biology.

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Section: Discussionmentioning

confidence: 74%

Molecular Signature Expands the Landscape of Driver Negative Thyroid Cancers

Bim

Carneiro

Buzatto

et al. 2021

Cancers

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“…An interesting finding is the strong stimulation of migration by EGF, despite the presence of oncogenic Ras (KRAS G12S ) in A549 cells (Pender et al, 2015). Although oncogenic Ras leads to hyperactivation of the MAPK cascade (Takacs et al, 2020), EGF treatment was nevertheless able to further increase Erk phosphorylation suggesting that mutated Ras leads to constitutive but submaximal activation of Erk via the MAPK cascade. Similar to the results presented here, dependency of EGF-stimulated migration on the MAPK pathway was previously reported in mesothelioma cell lines, albeit in the absence of oncogenic Ras (Schelch et al, 2018b).…”

Section: Discussionmentioning

confidence: 97%

EGF Induces Migration Independent of EMT or Invasion in A549 Lung Adenocarcinoma Cells

Schelch

Vogel

Schneller

et al. 2021

Front. Cell Dev. Biol.

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Tumors and the tumor microenvironment produce multiple growth factors that influence cancer cell behavior via various signal transduction pathways. Growth factors, like transforming growth factor β (TGFβ) and epidermal growth factor (EGF), have been shown to induce proliferation, migration, and invasion in different cell models. Both factors are frequently overexpressed in cancer and will often act in combination. Although both factors are being used as rational targets in clinical oncology, the similarities and differences of their contributions to cancer cell migration and invasion are not fully understood. Here we compared the impact of treating A549 lung adenocarcinoma cells with TGFβ, EGF, and both in combination by applying videomicroscopy, functional assays, immunoblotting, real-time PCR, and proteomics. Treatment with both factors stimulated A549 migration to a similar extent, but with different kinetics. The combination had an additive effect. EGF-induced migration depended on activation of the mitogen-activated protein kinase (MAPK) pathway. However, this pathway was dispensable for TGFβ-induced migration, despite a strong activation of this pathway by TGFβ. Proteome analysis (data are available via ProteomeXchange with identifier PXD023024) revealed an overlap in expression patterns of migration-related proteins and associated gene ontology (GO) terms by TGFβ and EGF. Further, only TGFβ induced the expression of epithelial to mesenchymal transition (EMT)-related proteins like matrix metalloproteinase 2 (MMP2). EGF, in contrast, made no major contribution to EMT marker expression on either the protein or the transcript level. In line with these expression patterns, TGFβ treatment significantly increased the invasive capacity of A549 cells, while EGF treatment did not. Moreover, the addition of EGF failed to enhance TGFβ-induced invasion. Overall, these data suggest that TGFβ and EGF can partly compensate for each other for stimulation of cell migration, but abrogation of TGFβ signaling may be more suitable to suppress cell invasion.

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“…Activated Ras interacts with the Ras-binding domain of the Tiam1 protein at the plasma membrane [26,143]. Tiam1 is a Rac exchange factor directly activated by Ras-GTP through a Ras-binding motif in its N terminus.…”

Section: Gefsmentioning

confidence: 99%

The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction

Soriano

Alcón-Pérez

Vicente‐Manzanares

et al. 2021

Genes

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Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway and the PI3K/AKT pathways, respectively. However, the myriad proteins close to the plasma membrane that activate or inhibit Ras make it a major regulator of many apparently unrelated pathways. On the other hand, Rho is weakly oncogenic by itself, but it critically regulates microfilament dynamics; that is, actin polymerization, disassembly and contraction. Polymerization is driven mainly by the Arp2/3 complex and formins, whereas contraction depends on myosin mini-filament assembly and activity. These two pathways intersect at numerous points: from Ras-dependent triggering of Rho activators, some of which act through PI3K, to mechanical feedback driven by actomyosin action. Here, we describe the main points of connection between the Ras and Rho pathways as they coordinately drive oncogenic transformation. We emphasize the biochemical crosstalk that drives actomyosin contraction driven by Ras in a Rho-dependent manner. We also describe possible routes of mechanical feedback through which myosin II activation may control Ras/Rho activation.

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The effects of mutant Ras proteins on the cell signalome

Cited by 45 publications

References 126 publications

Molecular Signature Expands the Landscape of Driver Negative Thyroid Cancers

Molecular Signature Expands the Landscape of Driver Negative Thyroid Cancers

EGF Induces Migration Independent of EMT or Invasion in A549 Lung Adenocarcinoma Cells

The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction

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