A requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation

Bentley, Carolyn; Jurinka, Stefanie S.; Kljavin, Noelyn M.; Vartanian, Steffan; Ramani, Sree R.; Gonzalez, Lino C.; Yu, Kebing; Modrušan, Zora; Du, Pan; Bourgon, Richard; Neve, Richard M.; Stokoe, David

doi:10.1042/bj20121578

Cited by 38 publications

(36 citation statements)

References 37 publications

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“…The latter could be the case in Ras-less fibroblasts, in which H-RasV12 is able to rescue viability in the absence of K-and N-Ras (30). In support of this notion, there is evidence demonstrating that oncogenic Ras requires other wild-type Ras isoforms for transformation (43)(44)(45)(46).…”

Section: Discussionsupporting

confidence: 56%

H-Ras Distribution and Signaling in Plasma Membrane Microdomains Are Regulated by Acylation and Deacylation Events

Agudo-Ibáñez

Herrero

Barbacid

et al. 2015

Molecular and Cellular Biology

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H-Ras must adhere to the plasma membrane to be functional. This is accomplished by posttranslational modifications, including palmitoylation, a reversible process whereby H-Ras traffics between the plasma membrane and the Golgi complex. At the plasma membrane, H-Ras has been proposed to occupy distinct sublocations, depending on its activation status: lipid rafts/detergent-resistant membrane fractions when bound to GDP, diffusing to disordered membrane/soluble fractions in response to GTP loading. Herein, we demonstrate that H-Ras sublocalization is dictated by its degree of palmitoylation in a cell type-specific manner. Whereas H-Ras localizes to detergent-resistant membrane fractions in cells with low palmitoylation activity, it locates to soluble membrane fractions in lineages where it is highly palmitoylated. Interestingly, in both cases GTP loading results in H-Ras diffusing away from its original sublocalization. Moreover, tilting the equilibrium between palmitoylation and depalmitoylation processes can substantially alter H-Ras segregation and, subsequently, its biochemical and biological functions. Thus, the palmitoylation/depalmitoylation balance not only regulates H-Ras cycling between endomembranes and the plasma membrane but also serves as a key orchestrator of H-Ras lateral diffusion between different types of plasma membrane and thereby of H-Ras signaling.

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Section: Discussionsupporting

confidence: 56%

H-Ras Distribution and Signaling in Plasma Membrane Microdomains Are Regulated by Acylation and Deacylation Events

Agudo-Ibáñez

Herrero

Barbacid

et al. 2015

Molecular and Cellular Biology

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“…Following EGF binding to its receptor and activation of tyrosine kinases, the K-ras protein becomes activated and transduces the activation signals to the nucleus by mitogen-activated protein kinases and PI3K/AKT-mediated cascades. The K-ras gene mutation in the NSCLC cells leads to the aberrant activation of the Akt signaling pathway (42). It appears that the constitutively activated Akt due to the K-ras gene mutation was not affected by the overexpression of maspin in A549 cells.…”

Section: Discussionmentioning

confidence: 96%

Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines

Zhou

Qin

Zhou

et al. 2015

International Journal of Molecular Medicine

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Abstract. Mammary serine protease inhibitor (maspin) is a tumor suppressor gene that is silenced in the majority of cancer cells during metastatic progression by transcriptional and epigenetic mechanisms. The function of maspin in non-small cell lung cancer cells (NSCLC) has not been clearly defined. In the present study, the expression of maspin in NSCLC cell lines, in particular, the adenocarcinoma cell lines, was heterogeneous. While the expression levels of maspin in PC-9 and H460 cell lines were intact, the expression of maspin in the A549 and SPC-A1 cells was hardly detected. Ectopic expression of maspin in A549 cells carrying the K-ras gene point mutation significantly inhibited cell migration and invasion abilities, which was associated with downregulated expression of matrix metalloproteinase-2 and integrin β1. Ectopic expression of maspin in SPC-A1 cells harboring the wild-type K-ras gene predominantly affected cell growth via targeting the AKT signaling molecules. Maspin functions differently in lung adenocarcinoma cells, possibly due to the varied molecular characteristics. IntroductionLung cancer is a leading cause of cancer mortality worldwide. Lung cancer is generally divided into non-small cell lung cancer cells (NSCLC) and SCLC, in which the NSCLC constitutes 80-85% of lung cancers. The three major NSCLC subtypes are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. NSCLC, which is characterized by slow tumor cell growth and dissemination, is refractory to chemotherapy and chest radiotherapy. Several driven genes have been identified in NSCLC, such as EGFR, c-MET and the ALK-EML4 fusion gene (1). Treatment for lung cancer is mainly based on tumor stage, tumor pathology and molecular pathology. Understanding thoroughly the molecular mechanism underlying the aberrant cellular events driving lung cancer progressions is crucial for developing novel treatments.Mammary serine protease inhibitor (maspin), also known as Serpin B5, was first identified in 1994 (2). Maspin belongs to the serine protease inhibitor superfamily, and is predominantly localized in the cytoplasm, but is also localized in the nucleus and membrane, and is secreted. The exact roles of maspin in cancer are far more complicated than initially thought due to the conflicting experimental and clinical data that have been reported. In prostate cancer, the expression of maspin is frequently absent (3). Overexpression of maspin is considered an independent factor in predicting a favorable prognosis in breast cancer and lung squamous cell cancer (4-6). However, it has been also reported that the increased nuclear maspin expression predicts a favorable prognosis, whereas the enhanced cytoplasmic expression is associated with early-relapsing and unfavorable prognosis in breast cancer (7). Enhanced expression of maspin is correlated with unfavorable prognosis in pancreatic, ovarian and colorectal cancer (8-10). High maspin expression correlates with an unfavorable outcome in colorectal cancer in stage III and IV, suggesting th...

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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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A requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation

Cited by 38 publications

References 37 publications

H-Ras Distribution and Signaling in Plasma Membrane Microdomains Are Regulated by Acylation and Deacylation Events

H-Ras Distribution and Signaling in Plasma Membrane Microdomains Are Regulated by Acylation and Deacylation Events

Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines

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

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