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Phosphorylation of iRhom2 controls stimulated proteolytic shedding by the metalloprotease ADAM17/TACE

ABSTRACT: TACE (TNFa Converting Enzyme), is responsible for cleavage (‘shedding’) of membrane-tethered signaling molecules such as TNF of EGFR ligands. TACE interacts with iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. In this study we analyze a new role for iRHOM2, where a fraction of the protein remains in the membrane and the phosphorylation of different residues in its cytoplasmatic tail is necessary for TACE shedding function.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Alfonso Bolado

LAB HEAD: Alexander von Kriegsheim

PROVIDER: PXD007763 | Pride | 2021-11-03

REPOSITORIES: Pride

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			Action	DRS
	DEAD_PMA7nov.raw	Raw
	Dead.raw	Raw
	Dead2.raw	Raw
	Dead_PMA2.raw	Raw
	Emptyvector.raw	Raw

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Publications

Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE.

Cavadas Miguel M Oikonomidi Ioanna I Gaspar Catarina J CJ Burbridge Emma E Badenes Marina M Félix Inês I Bolado Alfonso A Hu Tianyi T Bileck Andrea A Gerner Christopher C Domingos Pedro M PM von Kriegsheim Alex A Adrain Colin C

Cell reports 20171001 3

Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology i ...[more]

PMID: 29045841

Similar Datasets

Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE.

Project description:Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.

| S-EPMC5656746 | biostudies-literature

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Project description:Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte Activation Gene-3 (LAG3) signaling is regulated by A Disintegrin And Metalloprotease-10 (ADAM10) and ADAM17-mediated cell surface shedding. We developed and utilized mutant mice expressing a metalloprotease-resistance version of LAG3 that can be selectively expressed in T cell subsets. We sorted live T cells from tumors of mice bearing MC38 tumors following 3 treatments with either anti-PD1 or IgG control, and performed single-cell RNAseq using 10X 3' v2 reagents.

2020-05-22 | GSE150991 | GEO

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases is a Post-Translational Mechanism of Kinase Inhibitor Resistance.

Project description:Expression data from MDA-MB231 human breast cancer cells treated with metalloproteinase inhibitor (10uM BB94), MEK inhibitor (3uM PD325901), or DMSO control shows substantial overlap in the transcriptional responses arising from MEK and protease inhibition, suggesting a shared mechanism of action. Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTKs) including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of melanoma patients treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured non-invasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

2016-03-21 | GSE77868 | GEO

Wool shedding

Project description:Study of natural wool shedding

| PRJEB31930 | ENA

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Project description:Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

| PRJNA634347 | ENA

Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17.

Project description:Carbonic anhydrase IX (CA IX) is a transmembrane protein whose expression is strongly induced by hypoxia in a broad spectrum of human tumours. It is a highly active enzyme functionally involved in both pH control and cell adhesion. Its presence in tumours usually indicates poor prognosis. Ectodomain of CA IX is detectable in the culture medium and body fluids of cancer patients, but the mechanism of its shedding has not been thoroughly investigated. Here, we analysed several cell lines with natural and ectopic expression of CA IX to show that its ectodomain release is sensitive to metalloprotease inhibitor batimastat (BB-94) and that hypoxia maintains the normal rate of basal shedding, thus leading to concomitant increase in cell-associated and extracellular CA IX levels. Using CHO-M2 cells defective in shedding, we demonstrated that the basal CA IX ectodomain release does not require a functional TNFalpha-converting enzyme (TACE/ADAM17), whereas the activation of CA IX shedding by both phorbol-12-myristate-13-acetate and pervanadate is TACE-dependent. Our results suggest that the cleavage of CA IX ectodomain is a regulated process that responds to physiological factors and signal transduction stimuli and may therefore contribute to adaptive changes in the protein composition of tumour cells and their microenvironment.

| S-EPMC2361518 | biostudies-literature

ADAM17-mediated EGFR ligand shedding directs macrophage-promoted cancer cell invasion

Project description:ADAM17-mediated EGFR ligand shedding directs macrophage-promoted cancer cell invasion

| PRJNA875032 | ENA

(−)-Vinigrol Targets PDI-ADAM17 Module to Induce TNFR1 Shedding and Ameliorate Rheumatoid Arthritis in Mice

Project description:Our study indicates that targeting the PDI-ADAM17 signaling module to regulate the shedding of cytokine receptors by the chemical approach constitutes a novel strategy for alleviating RA

2023-03-10 | PXD040753 |

Peripheral blood transcriptome responses to Salmonella Typhimurium in pigs differing in Salmonella shedding phenotypes

Project description:Salmonella species infect many vertebrate species, and pigs colonized with Salmonella enterica serovar Typhimurium (ST) are usually asymptomatic, making detection of these Salmonella-carrier pigs difficult. The variable fecal shedding of this gram-negative bacteria in such pigs is an important cause of foodborne illness and zoonotic disease. To investigate gene pathways and biomarkers associated with the variance in Salmonella shedding following experimental inoculation, we have initiated the first analysis of the whole blood transcriptional response induced by Salmonella. A population of pigs (n=40) was inoculated with ST and the peripheral blood and feces were collected between 2 and 20 days post-inoculation. Two groups of pigs with either low shedding (LS) or persistent shedding (PS) phenotypes were identified. The global transcriptional changes in response to ST inoculation were identified by Affymetrix Genechip?analysis of peripheral blood RNA at day 0 and day 2 post-inoculation. Forty pigs (n=40) was inoculated with ST. Four low shedding (LS) pigs and six persistent shedding (PS) pigs were identified. Transcriptom of peripheral blood collected at 0 and 2 dpi were identified by Affymetrix Genechip analysis.

2011-05-28 | E-GEOD-27000 | biostudies-arrayexpress

A transcriptome study of a non-shedding fruit Elaeis oleifera palm

Project description:A comparative transcriptome analysis was performed to compare the fruit AZs of the non-shedding E. oleifera variant and from an individual of the same progeny that sheds its ripe fruit normally. The study provides evidence for widespread perturbation to gene expression in the AZ of the non-shedding variant, compared to the normal fruit-shedding control, and allows insight into abscission related functions.

2021-10-28 | GSE186050 | GEO

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