MAPK/ERK pathway

Summary

The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, such as mitogen-activated protein kinases (MAPKs), originally called extracellular signal-regulated kinases (ERKs), which communicate by adding phosphate groups to a neighboring protein (phosphorylating it), thereby acting as an "on" or "off" switch. When one of the proteins in the pathway is mutated, it can become stuck in the "on" or "off" position, a necessary step in the development of many cancers. In fact, components of the MAPK/ERK pathway were first discovered in cancer cells, and drugs that reverse the "on" or "off" switch are being

Official source

https://en.wikipedia.org/wiki/MAPK/ERK_pathway

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Role of Activin-A signaling in melanoma

Olivier Andreas Dubey

Cutaneous melanomas arise from transformed skin melanocytes. While accounting for only 1% of skin malignancies, melanoma is responsible for the majority of skin cancer-related deaths. Owing to lifestyle changes and increased exposure to sunlight, melanoma occurrence is on the rise in developed countries. Identification of the molecular mechanisms driving melanoma formation led to the development of new classes of therapeutics which revolutionized the standard of care. Among these, small molecule inhibitors targeting the MAPK pathway and immune checkpoint inhibitors resulted in unprecedented clinical success. Nevertheless, many patients still do not benefit from these therapies. Activin-A, a secreted ligand of the TGF-Î² superfamily, was recently found to be overexpressed in melanoma. However, whether Activin-A signaling promotes melanoma progression or therapy resistance is unknown. In this thesis, the contributions of autocrine and paracrine Activin-A signaling to melanoma growth are analyzed using lentiviral expression in melanoma cells of a constitutively active mutant type I Activin receptor (caALK4), of secreted Activin-A (gain-of-function), or of a ligand trap (loss-of-function). Paradoxically, while forced ALK4 signaling in melanoma grafts restored tumor suppression by inhibiting tumor cell survival and proliferation, transgenic Activin-A accelerated tumor growth. Conversely, expression of a ligand trap comprising the extracellular domain of Activin receptor IIB fused to human Fc (AIIB-Fc) slowed melanoma growth. Importantly, in immunodeficient Rag1-/- mice, effects of paracrine Activin-A gain and loss-of-function were abrogated, suggesting that Activin-A promotes melanoma progression by inhibiting the adaptive anti-tumor response. Flow cytometry analysis of tumor immune infiltrates combined with antibody-mediated cell depletion experiments confirmed that Activin-A promotes melanoma progression by inhibiting CD8+ tumor-infiltrating lymphocytes (TILs). Furthermore, inhibition of endogenous Activin-A sensitized a treatment-resistant melanoma model to immune checkpoint inhibition by anti-PD1 and anti-CTLA4 antibodies. Activin-A therefore emerges as a promising target to improve immunotherapy outcome in melanoma.

EPFL2019

Binding of Lassa virus perturbs extracellular matrix-induced signal transduction via dystroglycan

Stefan Kunz, Marie-Laurence Moraz, Christelle Pythoud, Françoise Gisou van der Goot Grunberg

The arenavirus Lassa virus (LASV) causes a severe haemorrhagic fever with high mortality in man. The cellular receptor for LASV is dystroglycan (DG). DG is a ubiquitous receptor for extracellular matrix (ECM) proteins, which cooperates with beta 1 integrins to control cellmatrix interactions. Here, we investigated whether LASV binding to DG triggers signal transduction, mimicking the natural ligands. Engagement of DG by LASV resulted in the recruitment of the adaptor protein Grb2 and the protein kinase MEK1 by the cytoplasmic domain of DG without activating the MEK/ERK pathway, indicating assembly of an inactive signalling complex. LASV binding to cells however affected the activation of the MEK/ERK pathway via a6 beta 1 integrins. The virus-induced perturbation of a6 beta 1 integrin signalling critically depended on high-affinity LASV binding to DG and DG's cytoplasmic domain, indicating that LASVreceptor binding perturbed signalling cross-talk between DG and beta 1 integrins.

Wiley-Blackwell2012

In this project, characterization of the MAPK signaling cascade was done using the terminal patterning of Drosophila embryo as an experimental system. MAPK acts downstream of the Torso receptor tyrosine kinase (RTK) whose activation is limited to the poles of the embryo. This results in a localized activation of MAPK which is essential for the specification of the embryonic termini. Active MAPK controls the expression of the tailless (tll) and huckebein (hkb) gap genes by downregulating a transcriptional repressor, Capicua (Cic). In this work we are interested in understanding the mechanisms that allow differential specification and precise positioning of gene expression boundaries. We quantitatively analyzed information flow from MAPK to Cic and the two target genes, tll and hkb, by constructing input-output maps in wild type embryos. Our results show that the sharp MAPK activation is translated into a graded gradient of Cic concentration and switch-like responses of tll and hkb genes. This indicates that the ultrasensitive response occurs at the level of the Cic repression which led us to test the hypothesis that Cic alone could be sufficient for tll and hkb boundary specification. However, data from mutants containing lower levels of Cic showed that boundaries of two genes become indistinguishable in terms of Cic concentration while still clearly different in terms of position. This suggests that MAPK downregulation of Cic alone is not sufficient to explain the observed localization and that, other factors are required for the robust patterning of the termini of the Drosophila embryo. To find the missing components of this regulatory system we have started an in vitro Yeast One Hybrid screen. This technique, allowing detection of protein-DNA interaction, was optimized for high-throughput screening. Together with a library Drosophila transcription factors we hope to identify the missing regulators of tll and hkb genes.

2010

Role of Activin-A signaling in melanoma

Olivier Andreas Dubey

EPFL2019