The Syk family of protein tyrosine kinases in T‐cell activation and development

Chu, David H.; Morita, Craig T.; Weiss, Arthur

doi:10.1111/j.1600-065x.1998.tb01238.x

Cited by 237 publications

(199 citation statements)

References 77 publications

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“…However, it cannot be ruled out that a low grade autophosphorylation of Syk may also play a role. Syk activation has been shown to involve several mechanisms, including a conformational change due to ITAM binding, autophosphorylation, and phosphorylation by other kinases (33)(34)(35). The relative importance of such mechanisms may be dictated by the modalities regulating Syk recruitment to different receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Syk/ZAP70 family PTKs are functionally coupled to several immunoreceptors and critically contribute to the signaling and functional ability of Ag and Fc receptors on T, B, and NK lymphocytes, myeloid cells, and platelets (33)(34)(35). Syk and ZAP70 are highly homologous; nevertheless, they do not seem to fulfill redundant roles.…”

Section: Discussionmentioning

confidence: 99%

“…The PTK-dependent activation of Syk by immunoreceptors may depend on autophosphorylation or be under the control of Src family kinases (33)(34)(35); no definitive information exists on the upstream events involved in Syk activation upon engagement of NKactivating receptors. To address the role of Src family kinases in CD69-triggered activation of Syk, we initially used the Src-selective pharmacological inhibitor PP2 (36).…”

Section: Cd69-triggered Activation Of Syk Is Mediated By Lckmentioning

confidence: 99%

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Src-Dependent Syk Activation Controls CD69-Mediated Signaling and Function on Human NK Cells

Pisegna

Zingoni

Pirozzi

et al. 2002

The Journal of Immunology

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CD69 C-type lectin receptor represents a functional triggering molecule on activated NK cells, capable of directing their natural killing function. The receptor-proximal signaling pathways activated by CD69 cross-linking and involved in CD69-mediated cytotoxic activity are still poorly understood. Here we show that CD69 engagement leads to the rapid and selective activation of the tyrosine kinase Syk, but not of the closely related member of the same family, ZAP70, in IL-2-activated human NK cells. Our results indicate the requirement for Src family kinases in the CD69-triggered activation of Syk and suggest a role for Lck in this event. We also demonstrate that Syk and Src family tyrosine kinases control the CD69-triggered tyrosine phosphorylation and activation of phospholipase Cγ2 and the Rho family-specific exchange factor Vav1 and are responsible for CD69-triggered cytotoxicity of activated NK cells. The same CD69-activated signaling pathways are also observed in an RBL transfectant clone, constitutively expressing the receptor. These data demonstrate for the first time that the CD69 receptor functionally couples to the activation of Src family tyrosine kinases, which, by inducing Syk activation, initiate downstream signaling pathways and regulate CD69-triggered functions on human NK cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cd69-triggered Activation Of Syk Is Mediated By Lckmentioning

confidence: 99%

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Src-Dependent Syk Activation Controls CD69-Mediated Signaling and Function on Human NK Cells

Pisegna

Zingoni

Pirozzi

et al. 2002

The Journal of Immunology

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“…We take ppTCR, but not pTCR, to be capable of recruiting and activating ZAP-70, which is a member of the Syk-family of protein tyrosine kinases. ZAP-70 is capable of binding doubly phosphorylated ITAMs through its two tandem Src homology 2 (SH2) domains, and much like Lck, ZAP-70 is activated through autophosphorylation Chu et al, 1998). We assume that when ZAP-70 is associated with ppTCR, autophosphorylation occurs through a process that is effectively spontaneous and first order.…”

Section: Model Formulationmentioning

confidence: 99%

Stochastic effects and bistability in T cell receptor signaling

Lipniacki

Hat

Faeder

et al. 2008

Journal of Theoretical Biology

119

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The stochastic dynamics of T cell receptor (TCR) signaling are studied using a mathematical model intended to capture kinetic proofreading (sensitivity to ligand-receptor binding kinetics) and negative and positive feedback regulation mediated respectively by the phosphatase SHP1 and the MAP kinase ERK. The model incorporates protein-protein interactions involved in initiating TCR-mediated cellular responses and reproduces several experimental observations about the behavior of TCR signaling, including robust responses to as few as a handful of ligands (agonist peptide-MHC complexes on an antigen-presenting cell), distinct responses to ligands that bind TCR with different lifetimes, and antagonism. Analysis of the model indicates that TCR signaling dynamics are marked by significant stochastic fluctuations and bistability, which is caused by the competition between the positive and negative feedbacks. Stochastic fluctuations are such that single-cell trajectories differ qualitatively from the trajectory predicted in the deterministic approximation of the dynamics. Because of bistability, the average of single-cell trajectories differs markedly from the deterministic trajectory. Bistability combined with stochastic fluctuations allows for switch-like responses to signals, which may aid T cells in making committed cell-fate decisions.

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“…Upon activation, Src-family PTK phosphorylate tyrosine residues contained in ITAMs located in the cytoplasmic tails of TCR-signaling chains such as TCR . The phosphorylated ITAMs are then recognized by the Src homology-2 domains of the Syk-family PTK, Zap70, which is thus recruited to the TCR-signaling complex and activated, in part, through transphosphorylation by Src-family PTK (10). Activated Zap70 phosphorylates the linker for activation of T cells transmembrane adapter protein which couples the TCR to the activation of transcription factors such as AP1, NF-B, and NFAT (3).…”

Section: T Cells Recognize Peptide Fragments Of Foreign Ags Togethermentioning

confidence: 99%

Normal TCR Signal Transduction in Mice That Lack Catalytically Active PTPN3 Protein Tyrosine Phosphatase

Bauler¹,

Hughes

Arimura

et al. 2007

The Journal of Immunology

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PTPN3 (PTPH1) is a cytoskeletal protein tyrosine phosphatase that has been implicated as a negative regulator of early TCR signal transduction and T cell activation. To determine whether PTPN3 functions as a physiological negative regulator of TCR signaling in primary T cells, we generated gene-trapped and gene-targeted mouse strains that lack expression of catalytically active PTPN3. PTPN3 phosphatase-negative mice were born in expected Mendelian ratios and exhibited normal growth and development. Furthermore, numbers and ratios of T cells in primary and secondary lymphoid organs were unaffected by the PTPN3 mutations and there were no signs of spontaneous T cell activation in the mutant mice with increasing age. TCR-induced signal transduction, cytokine production, and proliferation was normal in PTPN3 phosphatase-negative mice. This was observed using both quiescent T cells and recently stimulated T cells where expression of PTPN3 is substantially up-regulated. We conclude, therefore, that the phosphatase activity of PTPN3 is dispensable for negative regulation of TCR signal transduction and T cell activation.

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The Syk family of protein tyrosine kinases in T‐cell activation and development

Cited by 237 publications

References 77 publications

Src-Dependent Syk Activation Controls CD69-Mediated Signaling and Function on Human NK Cells

Src-Dependent Syk Activation Controls CD69-Mediated Signaling and Function on Human NK Cells

Stochastic effects and bistability in T cell receptor signaling

Normal TCR Signal Transduction in Mice That Lack Catalytically Active PTPN3 Protein Tyrosine Phosphatase

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