Journal
BIOCHEMICAL JOURNAL
Volume 454, Issue -, Pages 109-121Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20130485
Keywords
early signalling complex; extracellular-signal-regulated kinase (ERK); integrin; outside-in signalling; T-cell co-stimulation
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Funding
- G. Harold and Leila Y. Mathers Charitable Foundation
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Distinct signalling pathways producing diverse cellular outcomes can utilize similar subsets of proteins. For example, proteins from the TCR (T-cell receptor) ESC (early signalling complex) are also involved in interferon-alpha receptor signalling. Defining the mechanism for how these proteins function within a given pathway is important in understanding the integration and communication of signalling networks with one another. We investigated the contributions of the TCR ESC proteins Lck (lymphocyte-specific kinase), ZAP-70 (zeta-chain-associated protein of 70 kDa), Vav1, SLP-76 [SH2 (Src homology 2)-domain-containing leukocyte protein of 76 kDa] and LAT (linker for activation of T-cells) to integrin outside-in signalling in human T-cells. Lck, ZAP-70, SLP-76, Vav1 and LAT were activated by alpha 4 beta 1 outside-in signalling, but in a manner different from TCR signalling. TCR stimulation recruits ESC proteins to activate the mitogen-activated protein kinase ERK (extracellular-signal-regulated kinase). alpha 4 beta 1 outside-in-mediated ERK activation did not require TCR ESC proteins. However, alpha 4 beta 1 outside-in signalling induced CD25 and co-stimulated CD69 and this was dependent on TCR ESC proteins. TCR and alpha 4 beta 1 outside-in signalling are integrated through the common use of TCR ESC proteins; however, these proteins display functionally distinct roles in these pathways. These novel insights into the cross-talk between integrin outside-in and TCR signalling pathways are highly relevant to the development of therapeutic strategies to overcome disease associated with T-cell deregulation.
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