Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation

Shankha Satpathy; Sebastian A Wagner; Petra Beli; Rajat Gupta; Trine A Kristiansen; Dessislava Malinova; Chiara Francavilla; Pavel Tolar; Gail A Bishop; Bruce S Hostager; Chunaram Choudhary

doi:10.15252/msb.20145880

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Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation

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Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation

Shankha Satpathy, Sebastian A Wagner, Petra Beli, Rajat Gupta, Trine A Kristiansen, Dessislava Malinova, Chiara Francavilla, Pavel Tolar, Gail A Bishop, Bruce S Hostager, …

Molecular systems biology, Vol.11(6), pp.810-n/a

06/02/2015

DOI: 10.15252/msb.20145880

PMCID: PMC4501846

PMID: 26038114

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Abstract

B-cell receptor (BCR) signaling is essential for the development and function of B cells; however, the spectrum of proteins involved in BCR signaling is not fully known. Here we used quantitative mass spectrometry-based proteomics to monitor the dynamics of BCR signaling complexes (signalosomes) and to investigate the dynamics of downstream phosphorylation and ubiquitylation signaling. We identify most of the previously known components of BCR signaling, as well as many proteins that have not yet been implicated in this system. BCR activation leads to rapid tyrosine phosphorylation and ubiquitylation of the receptor-proximal signaling components, many of which are co-regulated by both the modifications. We illustrate the power of multilayered proteomic analyses for discovering novel BCR signaling components by demonstrating that BCR-induced phosphorylation of RAB7A at S72 prevents its association with effector proteins and with endo-lysosomal compartments. In addition, we show that BCL10 is modified by LUBAC-mediated linear ubiquitylation, and demonstrate an important function of LUBAC in BCR-induced NF-κB signaling. Our results offer a global and integrated view of BCR signaling, and the provided datasets can serve as a valuable resource for further understanding BCR signaling networks.

Proteomics

Membrane Proteins - genetics

Humans

Signal Transduction - genetics

Ubiquitin-Protein Ligases - biosynthesis

Membrane Proteins - biosynthesis

Phosphorylation - genetics

NF-kappa B - genetics

NF-kappa B - biosynthesis

B-Cell CLL-Lymphoma 10 Protein

Adaptor Proteins, Signal Transducing - genetics

HEK293 Cells

Receptors, Antigen, B-Cell - genetics

Adaptor Proteins, Signal Transducing - biosynthesis

Receptors, Antigen, B-Cell - biosynthesis

HeLa Cells

Ubiquitin-Protein Ligases - genetics

B-Lymphocytes - metabolism

Ubiquitination - genetics

Details

Title: Subtitle: Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation
Creators: Shankha Satpathy - Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Sebastian A Wagner - Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Petra Beli - Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Rajat Gupta - Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Trine A Kristiansen - Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Dessislava Malinova - Division of Immune Cell Biology, MRC National Institute for Medical Research, Mill Hill, London, UK
Chiara Francavilla - Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Pavel Tolar - Division of Immune Cell Biology, MRC National Institute for Medical Research, Mill Hill, London, UK
Gail A Bishop - Department of Microbiology, Graduate Program in Immunology and Department of Internal Medicine, University of Iowa, Iowa City, IA, USA VAMC, Iowa City, IA, USA
Bruce S Hostager - Department of Pediatrics, University of Iowa, Iowa City, IA, USA
Chunaram Choudhary - Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark chuna.choudhary@cpr.ku.dk
Resource Type: Journal article
Publication Details: Molecular systems biology, Vol.11(6), pp.810-n/a
DOI: 10.15252/msb.20145880
PMID: 26038114
PMCID: PMC4501846
NLM abbreviation: Mol Syst Biol
ISSN: 1744-4292
eISSN: 1744-4292
Publisher: England
Grant note: P30 ES005605 / NIEHS NIH HHS U117597138 / Medical Research Council
Language: English
Date published: 06/02/2015
Academic Unit: Microbiology and Immunology; President
Record Identifier: 9984001138702771

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