Neutrophil signaling: Integrin and Syk in an adaptor-coupled ITAM
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The phosphorylation of adaptors containing the immunoreceptor tyrosine-based activation motif (ITAMs) by Src kinases is the first intracellular step of integrin signaling in neutrophils and macrophages.
The innate immune response — including the adhesion of phagocytes to invading pathogens and the release of antimicrobial proteins — is mediated by the binding of chemokines and growth factors to integrin transmembrane receptors. Syk tyrosine kinases are usually considered to be the first intracellular target of integrin signaling. However, Src family kinases phosphorylate ITAMs during the first signaling step of the adaptive immune response elicited by antigen binding to immune receptors such as the T-cell receptor (TCR), leading to the activation of Syk kinases. In Nature Immunology, Mócsai and colleagues demonstrate in vivo for the first time under physiological conditions that Src phosphorylation of the ITAM-containing adaptors DAP12 and FcRγ is also required for integrin signaling in neutrophils and macrophages.
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Neutrophils from mice deficient in both DAP12 and FcRγ adaptor proteins (DF double-knockout) did not show integrin-mediated immune responses, including tumor necrosis factor α (TNF-α)-induced respiratory bursts. DF double-knockout neutrophils did not reveal defects in adhesion-independent responses to TNF-α, such as actin polymerization and p38 phosphorylation, showing that adhesion-dependent integrin signaling was specifically disrupted. Phosphorylated Syk could not be detected in DF double-knockout neutrophils nor in Src-kinase-null neutrophils, indicating a connection between adaptor function, Src activity and Syk phosphorylation.
To elucidate the molecular details of this connection, the authors performed rescue experiments with wild-type and mutant versions of Syk and DAP12 in Syk-knockout or DF-double-knockout neutrophils. In the mutants, DAP12 was not phosphorylated, and Syk did not bind to phosphorylated ITAMs. Neither of these mutants were able to restore a functional response in the DF double-knockout or Syk neutrophil knockouts. As mature neutrophils have a life span too limited for protein activity analysis, the authors engineered hematopoietic stem cells expressing a tag allowing their isolation after injection into lethally irradiated mice. Similar results were obtained with double knock-out macrophages, suggesting that ITAM-mediated integrin signaling may be a property of all phagocytic lymphocytes.
This study demonstrates that integrin signaling in neutrophils mirrors and macrophages immunoreceptor signaling, linking integrin clustering and phosphorylation of adaptor ITAMs by Src kinases to Syk kinase activation. In contrast to immunoreceptors, integrins are not directly associated with adaptor proteins, and future studies may reveal how activated integrin clusters signal to the adaptor proteins in this pathway.
Mirko von Elstermann
Functional Glycomics Gateway
References
- Mócsai A. et al. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nature Immunology 7, 1326-1333 (2006) | Article | PubMed |
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