RAF kinases are stabilized and required for dendritic cell differentiation and function

Riegel, Kristina; Schlöder, Janine; Sobczak, Marco; Jonuleit, Helmut; Thiede, Bernd; Schild, Hansjörg; Rajalingam, Krishnaraj

doi:10.1038/s41418-019-0416-4

Cited by 15 publications

(18 citation statements)

References 44 publications

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“…Despite the central roles played by MAPK signaling in immune responses (Stupack et al, 2000), the impact of Ras-Erk signaling on the diverse functions of immune cells has only started to be understood (Ebert et al, 2016;Scheele et al, 2007). Furthermore, in primary dendritic cells (DCs), Ras-Erk signaling remains largely unexplored (Riegel et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma-infected dendritic cells

Ólafsson

Hoeve

Li-Wang

et al. 2020

Journal of Cell Science

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Ras-Erk MAPK signaling controls many of the principal pathways involved in metazoan cell motility, drives metastasis of multiple cancer types and is targeted in chemotherapy. However, its putative roles in immune cell functions or in infections have remained elusive. Here, using primary dendritic cells (DCs) in an infection model with the protozoan Toxoplasma gondii, we show that two pathways activated by infection converge on Ras-Erk MAPK signaling to promote migration of parasitized DCs. We report that signaling through the receptor tyrosine kinase Met (also known as HGF receptor) contributes to T. gondii-induced DC hypermotility. Furthermore, voltage-gated Ca 2+ channel (VGCC, subtype Ca V 1.3) signaling impacted the migratory activation of DCs via calmodulin-calmodulin kinase II. We show that convergent VGCC signaling and Met signaling activate the GTPase Ras to drive Erk1 and Erk2 (also known as MAPK3 and MAPK1, respectively) phosphorylation and hypermotility of T. gondii-infected DCs. The data provide a molecular basis for the hypermigratory mesenchymal-to-amoeboid transition (MAT) of parasitized DCs. This emerging concept suggests that parasitized DCs acquire metastasislike migratory properties that promote infection-related dissemination.

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Section: Introductionmentioning

confidence: 99%

Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma-infected dendritic cells

Ólafsson

Hoeve

Li-Wang

et al. 2020

Journal of Cell Science

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“…Preclinical experiments, carried out on human and mouse DC cells, have detected a reduced or lack of DCs’ ability to recruit T cells after treatment with RAF kinase inhibitors. These experiments, therefore, open possible new therapeutic scenarios, not only in melanoma, considering the negative effects of pan-RAF inhibitors on the immune response modulation [ 170 ].…”

Section: Tme Implications In Drug Resistance For Melanomamentioning

confidence: 99%

Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

Falcone

Cognetti

Bazzichetto

et al. 2020

Cancers

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Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase kinase (MEK), v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy.

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“…The GSK3 kinase (ergo its two isoforms, GSK3A and GSK3B) have been proposed to be a good candidate for immunotherapy, as its inhibitors promote an immune response against a wide range of human cancer cells, including melanoma 53. The RAF kinases (ARAF, BRAF, CRAF) are intensively studied due to their role in tumorigenesis regulation, however, it was also found that they are required for the differentiation and function of dendritic cells 54 . PRKCA was shown to be involved in the proliferation and differentiation of immune cells, although its function shows both pro-and anti-oncogenic properties 55 .…”

Section: Study Of the Melanoma Kinome In The Context Of Tumor Proliferationmentioning

confidence: 99%

Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

Kim

Szeitz

et al. 2021

Preprint

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Malignant melanoma (MM) develops from the melanocytes and in its advanced stage is the most aggressive type of skin cancer. Here we report a comprehensive analysis on a prospective cohort study, including non-tumor, primary and metastasis tissues (n=77) with the corresponding plasma samples (n=56) from patients with malignant melanoma. The tumors and surrounding tissues were characterized with a combination of high-throughput analyses including quantitative proteomics, phosphoproteomics, acetylomics, and whole exome sequencing (WES) combined with in-depth histopathology analysis. Melanoma cell proliferation highly correlates with dysregulation at the proteome, at the posttranslational- and at the transcriptome level. Some of the changes were also verified in the plasma proteome. The metabolic reprogramming in melanoma includes upregulation of the glycolysis and the oxidative phosphorylation, and an increase in glutamine consumption, while downregulated proteins involved in the degradation of amino acids, fatty acids, and the extracellular matrix (ECM) receptor interaction. The pathways most dysregulated in MM including the MAP kinases-, the PI3K-AKT signaling, and the calcium homeostasis, are among the most affected by mutations, thus, dysregulation in these pathways can be manifested as drivers in melanoma development and progression. The phosphoproteome analysis combined with target-based prediction mapped 75% of the human kinome. Melanoma cell proliferation was driven by two key factors: i) metabolic reprogramming leading to upregulation of the glycolysis and oxidative phosphorylation, supported by HIF-1 signaling pathway and mitochondrial translation; and ii) a dysregulation of the immune system response, which was mirrored by immune system processes in the plasma proteome. Regulation of the melanoma acetylome and expression of deacetylase enzymes discriminated between groups based on tissue origin and proliferation, indicating a way to guide the successful use of HDAC inhibitors in melanoma. The disease progression toward metastasis is driven by the downregulation of the immune system response, including MHC class I and II, which allows tumors to evade immune surveillance. Altogether, new evidence is provided at different molecular levels to allow improved understanding of the melanoma progression, ultimately contributing to better treatment strategies.

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RAF kinases are stabilized and required for dendritic cell differentiation and function

Cited by 15 publications

References 44 publications

Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma-infected dendritic cells

Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma-infected dendritic cells

Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

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