Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling

Young, Amy; Lou, David Y.; McCormick, Frank

doi:10.1158/2159-8290.cd-12-0231

Cited by 189 publications

(186 citation statements)

References 49 publications

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“…Further, cooperative loss of these feedback mechanisms was shown to promote Ras-induced leukemogenesis (50). EphA2 has been suggested to be one such negative feedback regulator inhibiting KRAS downstream signaling pathways (30,55). Our results show that loss of EphA2 promotes cell proliferation by activating proliferative signaling and transcription programs.…”

Section: Discussionmentioning

confidence: 53%

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Lung adenocarcinoma, a major form of non-small cell lung cancer, is the leading cause of cancer deaths. The Cancer Genome Atlas analysis of lung adenocarcinoma has identified a large number of previously unknown copy number alterations and mutations, requiring experimental validation before use in therapeutics. Here, we describe an shRNA-mediated high-throughput approach to test a set of genes for their ability to function as tumor suppressors in the background of mutant KRas and WT Tp53. We identified several candidate genes from tumors originated from lentiviral delivery of shRNAs along with Cre recombinase into lungs of Loxp-stop-Loxp-KRas mice. Ephrin receptorA2 (EphA2) is among the top candidate genes and was reconfirmed by two distinct shRNAs. By generating knockdown, inducible knockdown and knockout cell lines for loss of EphA2, we showed that negating its expression activates a transcriptional program for cell proliferation. Loss of EPHA2 releases feedback inhibition of KRAS, resulting in activation of ERK1/2 MAP kinase signaling, leading to enhanced cell proliferation. Intriguingly, loss of EPHA2 induces activation of GLI1 transcription factor and hedgehog signaling that further contributes to cell proliferation. Small molecules targeting MEK1/2 and Smoothened hamper proliferation in EphA2-deficient cells. Additionally, in EphA2 WT cells, activation of EPHA2 by its ligand, EFNA1, affects KRAS–RAF interaction, leading to inhibition of the RAS-RAF-MEK-ERK pathway and cell proliferation. Together, our studies have identified that (i) EphA2 acts as a KRas cooperative tumor suppressor by in vivo screen and (ii) reactivation of the EphA2 signal may serve as a potential therapeutic for KRas-induced human lung cancers.

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Section: Discussionmentioning

confidence: 53%

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, even a high expression of wild type KRAS protein is not itself able to induce metabolic reprogramming. This observation is interesting in light of recent work by Young et al, who demonstrated that both the mutant and wild type KRAS alleles play distinct roles in regulating signaling through the epidermal growth factor pathway (61).…”

Section: Discussionmentioning

confidence: 82%

Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer

Hutton

Wang

Zimmerman

et al. 2016

Molecular & Cellular Proteomics

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Metabolic reprogramming, in which altered utilization of glucose and glutamine supports rapid growth, is a hallmark of most cancers. Mutations in the oncogenes KRAS and BRAF drive metabolic reprogramming through enhanced glucose uptake, but the broader impact of these mutations on pathways of carbon metabolism is unknown. Global shotgun proteomic analysis of isogenic DLD-1 and RKO colon cancer cell lines expressing mutant and wild type KRAS or BRAF, respectively, failed to identify significant differences (at least 2-fold) in metabolic protein abundance. However, a multiplexed parallel reaction monitoring (PRM) strategy targeting 73 metabolic proteins identified significant protein abundance increases of 1.25-twofold in glycolysis, the nonoxidative pentose phosphate pathway, glutamine metabolism, and the phosphoserine biosynthetic pathway in cells with KRAS G13D mutations or BRAF V600E mutations. These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein.In DLD-1 cells, these effects were independent of the ratio of KRAS G13D to KRAS wild type protein. A study of 8 KRAS wild type and 8 KRAS mutant human colon tumors confirmed the association of increased expression of glycolytic and glutamine metabolic proteins with KRAS mutant status. Metabolic reprogramming is driven largely by modest (<2-fold) alterations in protein expression, which are not readily detected by the global profiling methods most commonly employed in proteomic studies. The results indicate the superiority of more precise, multiplexed, pathway-targeted analyses to study functional proteome systems. Data are available through MassIVE Accession MSV000079486 at

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“…Recent studies demonstrated that wild-type Ras proteins contribute to tumorigenesis in Ras-mutant cancer cells (21)(22)(23)(24). However, the oncogenic roles of Ras in Ras wild-type cancers have yet to be established.…”

Section: Discussionmentioning

confidence: 99%

Ras–MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells

Lee¹,

Cao²,

Pham

et al. 2017

Molecular Cancer Therapeutics

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Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras-MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Furthermore, exogenous DNA damage promotes Chk1 dependency, and pharmacologic Chk1 inhibition combined with genotoxic chemotherapy potentiates a DNA damage response and tumor cell killing. These findings reveal a mechanism-based diagnostic strategy to identify cancer patients that may benefit from Chk1-targeted therapy.

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Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling

Cited by 189 publications

References 49 publications

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer

Ras–MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells

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