“RAF” neighborhood: Protein–protein interaction in the Raf/Mek/Erk pathway

Cseh, Botond; Doma, Eszter; Baccarini, Manuela

doi:10.1016/j.febslet.2014.06.025

Cited by 91 publications

(90 citation statements)

References 140 publications

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“…See also Figure S5. pathway must regulate signaling downstream of FLT3 in these cells, such as the MAPK-Erk pathway, which has been demonstrated to be activated by FLT3 (Scheffler et al, 2014) and is also target of Ras (Cseh et al, 2014). Interestingly, tissue-resident pre-DCs had already acquired an organ-specific signature to a certain degree, as lung pre-DCs partially depended on p110g, whereas this was not the case for pre-DCs in the BM.…”

Section: Discussionmentioning

confidence: 99%

PI3-Kinase-γ Has a Distinct and Essential Role in Lung-Specific Dendritic Cell Development

Nobs

Schneider

Dietrich³

et al. 2015

Immunity

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Development of dendritic cells (DCs) commences in the bone marrow, from where pre-DCs migrate to peripheral organs to differentiate into mature DCs in situ. However, the factors that regulate organ-specific differentiation to give rise to tissue-specific DC subsets remain unclear. Here we show that the Ras-PI3Kγ-Akt-mTOR signaling axis acted downstream of FLT3L signaling and was required for development of lung CD103(+) DCs and, to a smaller extent, for lung CD11b(+) DCs, but not related DC populations in other non-lymphoid organs. Furthermore, we show that in lymphoid organs such as the spleen, DCs depended on a similar signaling network to respond to FLT3 ligand with overlapping and partially redundant roles for kinases PI3Kγ and PI3Kδ. Thus we identified PI3Kγ as an essential organ-specific regulator of lung DC development and discovered a signaling network regulating tissue-specific DC development mediated by FLT3.

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Section: Discussionmentioning

confidence: 99%

PI3-Kinase-γ Has a Distinct and Essential Role in Lung-Specific Dendritic Cell Development

Nobs

Schneider

Dietrich³

et al. 2015

Immunity

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“…RAF kinases, including A-RAF, B-RAF, and C-RAF, are the direct KRAS effectors that mediate MAPK activation. B-RAF is generally regarded as the dominant mediator for oncogenic KRAS signaling to activate MAPK (Cseh et al 2014). Accordingly, in a Kras-driven PDAC GEMM, C-Raf deletion had minimal effect on tumor development (Eser et al 2013), which is in contrast to significant tumor suppression in an oncogenic Kras-driven lung cancer model with C-Raf deletion (Blasco et al 2011;Karreth et al 2011).…”

Section: Kras Signaling Surrogates In Tumor Development and Maintenancementioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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“…Since elevated AKT and MAP kinase activities are frequently observed in human cancers (Cseh et al, 2014;Manning and Cantley, 2007), we tested whether Salmonella could employ the same host pathways to initiate transformation. The Results are representative of three independent experiments.…”

Section: Salmonella Enterica-mediated Activation Of Akt and Map Kinasmentioning

confidence: 99%

Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma

Scanu

Spaapen

Bakker

et al. 2015

Cell Host & Microbe

210

213

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Cancer is fueled by deregulation of signaling pathways in control of cellular growth and proliferation. These pathways are also targeted by infectious pathogens en route to establishing infection. Gallbladder carcinoma (GBC) is frequent in the Indian subcontinent, with chronic Salmonella enterica serovar Typhi infection reported as a significant risk factor. However, direct association and causal mechanisms between Salmonella Typhi infection and GBC have not been established. Deconstructing the epidemiological association between GBC and Salmonella Typhi infection, we show that Salmonella enterica induces malignant transformation in predisposed mice, murine gallbladder organoids, and fibroblasts, with TP53 mutations and c-MYC amplification. Mechanistically, activation of MAPK and AKT pathways, mediated by Salmonella enterica effectors secreted during infection, is critical to both ignite and sustain transformation, consistent with observations in GBC patients from India. Collectively, our findings indicate that Salmonella enterica can promote transformation of genetically predisposed cells and is a causative agent of GBC.

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“RAF” neighborhood: Protein–protein interaction in the Raf/Mek/Erk pathway

Cited by 91 publications

References 140 publications

PI3-Kinase-γ Has a Distinct and Essential Role in Lung-Specific Dendritic Cell Development

PI3-Kinase-γ Has a Distinct and Essential Role in Lung-Specific Dendritic Cell Development

Genetics and biology of pancreatic ductal adenocarcinoma

Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma

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