CD25 and CD69 induction by α4β1 outside-in signalling requires TCR early signalling complex proteins

Ann Marie Cimo, Zamal Ahmed, Bradley W. Mcintyre, Dorothy E. Lewis, John E. Ladbury

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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-α 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 (ζ -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 α4β1 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-signalregulated kinase). α4β1 outside-in-mediated ERK activation did not require TCR ESC proteins. However, α4β1 outsidein signalling induced CD25 and co-stimulated CD69 and this was dependent on TCR ESC proteins. TCR and α4β1 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.

Original languageEnglish (US)
Pages (from-to)109-121
Number of pages13
JournalBiochemical Journal
Volume454
Issue number1
DOIs
StatePublished - Aug 15 2013

Keywords

  • Early signalling complex
  • Extracellular-signal-regulated kinase (ERK)
  • Integrin
  • Outside-in signalling
  • T-cell co-stimulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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