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  Modulation of TCR responsiveness by the Grb2-family adaptor, Gads.

Lugassy, J., Corso, J., Beach, D., Petrik, T., Oellerich, T., Urlaub, H., et al. (2015). Modulation of TCR responsiveness by the Grb2-family adaptor, Gads. Cellular Signalling, 27(1), 125-134. doi:10.1016/j.cellsig.2014.10.005.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-B99D-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-1C4D-1
Genre: Journal Article

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2087994.pdf (Publisher version), 2MB
 
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 Creators:
Lugassy, J., Author
Corso, J.1, Author              
Beach, D., Author
Petrik, T., Author
Oellerich, T.1, Author              
Urlaub, H.1, Author              
Yablonski, D., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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Free keywords: T cell receptor (TCR); Adaptor protein; Transcription activator-like effector nuclease (TALEN); Gads
 Abstract: T cell antigen receptor (TCR) signaling depends on three interacting adaptor proteins: SLP-76, Gads, and LAT. Their mechanisms of signaling have been extensively explored, with the aid of fortuitously isolated LAT- and SLP-76-deficient T cell lines, but no such tools were available for Gads, a Grb2-family adaptor that bridges the TCR-inducible interaction between SLP-76 and LAT. TALEN-directed genome editing was applied to disrupt the first coding exon of human Gads in the Jurkat T cell line. Gads was dispensable for TCR-induced phosphorylation of SLP-76, but was a dose-dependent amplifier of TCR-induced CD69 expression. Gads conferred responsiveness to weak TCR stimuli, leading to PLC-gamma 1 phosphorylation and calcium flux. TALEN-derived, Gads-deficient T cell lines provide a uniquely tractable genetic platform for exploring its regulatory features, such as Gads phosphorylation at T262, which we observed by mass spectrometry. Upon mutation of this site, TCR responsiveness and sensitivity to weak TCR stimuli were increased. This study demonstrates the feasibility of TALEN-based reverse genetics in Jurkat T cells, while enriching our understanding of Gads as a regulated modulator of TCR sensitivity.

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Language(s): eng - English
 Dates: 2014-10-232015-01
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.cellsig.2014.10.005
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Title: Cellular Signalling
Source Genre: Journal
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Pages: - Volume / Issue: 27 (1) Sequence Number: - Start / End Page: 125 - 134 Identifier: -