Search results for "Phosphorylation"

GRIP1 Binds to ApoER2 and EphrinB2 to Induce Activity-Dependent AMPA Receptor Insertion at the Synapse

2017

Summary Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in response to neuronal activity is critical for synaptic function and plasticity. Here, we show that neuronal activity induces the binding of ephrinB2 and ApoER2 receptors at the postsynapse to regulate de novo insertion of AMPA receptors. Mechanistically, the multi-PDZ adaptor glutamate-receptor-interacting protein 1 (GRIP1) binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors. Phosphorylation of ephrinB2 in a serine residue (Ser-9) is essential for the stability of such a complex. In vivo, a mutation on ephrinB2 Ser-9 in mice results in a complete disruption…

MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition

2017

Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number. We tested this hypothesis by generating isogenic cell lines from NCI-H1975 cells, which co-express L858R and T790M EGFR mutations, namely H1975L858R/T790M (EGFR TKI resista…

Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

2016

NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) a…

Nuclear signaling of plant MAPKs

2018

This article is part of the research topic: Post-Translational Modifications in Plant Nuclear Signaling: Novel Insights into Responses to Environmental Changes; International audience; Mitogen-activated protein kinases (MAPKs) are conserved protein kinases in eukaryotes that establish signaling modules where MAPK kinase kinases (MAPKKKs) activate MAPK kinases (MAPKKs) which in turn activate MAPKs. In plants, they are involved in the signaling of multiple environmental stresses and developmental programs. MAPKs phosphorylate their substrates and this post-translational modification (PTM) contributes to the regulation of proteins. PTMs may indeed modify the activity, subcellular localization,…

Cellular complexity in MAPK signaling in plants: Questions and emerging tools to answer them

2018

International audience; Mitogen activated protein kinase (MAPK) cascades play an important role in many aspects of plant growth, development, and environmental response. Because of their central role in many important processes, MAPKs have been extensively studied using biochemical and genetic approaches. This work has allowed for the identification of the MAPK genes and proteins involved in a number of different signaling pathways. Less well developed, however, is our understanding of how MAPK cascades and their corresponding signaling pathways are organized at subcellular levels. In this review, we will provide an overview of plant MAPK signaling, including a discussion of what is known a…

2020

The cell cycle is controlled by microtubule-associated serine/threonine kinase-like (MASTL), which phosphorylates the cAMP-regulated phosphoproteins 19 (ARPP19) at S62 and 19e/α-endosulfine (ENSA) at S67and converts them into protein phosphatase 2A (PP2A) inhibitors. Based on initial proteomic data, we hypothesized that the MASTL-ENSA/ARPP19-PP2A pathway, unknown until now in platelets, is regulated and functional in these anucleate cells. We detected ENSA, ARPP19 and various PP2A subunits (including seven different PP2A B-subunits) in proteomic studies of human platelets. ENSA-S109/ARPP19–S104 were efficiently phosphorylated in platelets treated with cAMP- (iloprost) and cGMP-elevating (NO…

Arrestin-β-1 Physically Scaffolds TSH and IGF1 Receptors to Enable Crosstalk

2019

Endogenously expressed TSH receptors (TSHRs) on orbital fibroblasts of patients with Graves ophthalmopathy (GO) use crosstalk with IGF1 receptors (IGF1R) to synergistically stimulate secretion of hyaluronan (HA), a major component of GO pathology. We previously showed crosstalk occurred upstream of mitogen-activated protein kinase (ERK) phosphorylation. Because other G protein-coupled receptors engage arrestin-β-1 (ARRB1) and ERK, we tested whether ARRB1 was a necessary component of TSHR/IGF1R crosstalk. HA secretion was stimulated by the TSHR-stimulating monoclonal antibodies M22 and KSAb1, or immunoglobulins from patients with GO (GO-Igs). Treatment with M22, as previously shown, resulted…

The Role of ERK Signaling in Experimental Autoimmune Encephalomyelitis

2017

Extracellular signal-regulated kinase (ERK) signaling plays a crucial role in regulating immune cell function and has been implicated in autoimmune disorders. To date, all commercially available inhibitors of ERK target upstream components, such as mitogen-activated protein (MAP) kinase/ERK kinase (MEKs), but not ERK itself. Here, we directly inhibit nuclear ERK translocation by a novel pharmacological approach (Glu-Pro-Glu (EPE) peptide), leading to an increase in cytosolic ERK phosphorylation during T helper (Th)17 cell differentiation. This was accompanied by diminished secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine influencing the encephalitogenicity …

AMPK phosphorylation modulates pain by activation of NLRP3 inflammasome

2016

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p38α regulates actin cytoskeleton and cytokinesis in hepatocytes during development and aging.

2017

[Background]: Hepatocyte poliploidization is an age-dependent process, being cytokinesis failure the main mechanism of polyploid hepatocyte formation. Our aim was to study the role of p38α MAPK in the regulation of actin cytoskeleton and cytokinesis in hepatocytes during development and aging. [Methods]: Wild type and p38α liver-specific knock out mice at different ages (after weaning, adults and old) were used. [Results]: We show that p38α MAPK deficiency induces actin disassembly upon aging and also cytokinesis failure leading to enhanced binucleation. Although the steady state levels of cyclin D1 in wild type and p38α knock out old livers remained unaffected, cyclin B1- a marker for G2/M…