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-signal-regulated kinase). α4β1 outside-in-mediated ERK activation did not require TCR ESC proteins. However, α4β1 outside-in 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.
Highlights
Integrins are critical for T-cell function, including T-cell recirculation and recruitment into inflammatory sites, the formation of conjugates with antigen-presenting cells and cytokine secretion
The effect of integrin outside-in signalling on the activation of T-cell receptor (TCR) early signalling complex (ESC) proteins in Jurkat cells was determined using the specific anti-α4β1 integrin antibody 19H8 followed by the addition of a secondary cross-linker (2 )
SH2-domaincontaining leukocyte protein of 76 kDa (SLP-76) is activated in response to integrin α4β1 outside-in signalling, but it is not involved in Vav1 phosphorylation (Figure 3E). Perhaps this is not surprising, because the TCR-stimulated SLP-76–Vav1 interaction is dependent on ζ-chainassociated protein of 70 kDa (ZAP-70) kinase function, which is not active in integrin signalling. These results indicate that α4β1 outside-in signalling leads to the phosphorylation of the TCR ESC proteins lymphocyte-specific kinase (Lck), ZAP-70, Vav1, SLP-76 and linker for activation of T-cells (LAT) and this pathway utilizes a subset of proteins common to TCR signalling
Summary
Integrins are critical for T-cell function, including T-cell recirculation and recruitment into inflammatory sites, the formation of conjugates with antigen-presenting cells and cytokine secretion. Integrins play a major role in T-cell activation by providing co-stimulatory signals that synergize with early signals initiated by the TCR (T-cell receptor). The predominant integrins expressed on T-cells include VLA-4 (very late antigen-4; α4β1) and LFA-1 (lymphocyte-functionassociated antigen 1; αLβ2). Integrins are capable of signalling bidirectionally in pathways referred to as inside-out and outside-in signalling. Inside-out signalling can be induced by intracellular signals triggered by the engagement of other cellsurface receptors, such as TCR and chemokine receptors. In outside-in signalling, integrins transmit signals from the exterior environment to the interior of the cell upon integrin ligand binding
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