The influence of the src‐family kinases, Lck and Fyn, on T cell differentiation, survival and activation

Zamoyska, Rose; Basson, M. Albert; Filby, Andrew; Legname, Giuseppe; Lovatt, Matthew; Seddon, Benedict

doi:10.1034/j.1600-065x.2003.00015.x

Cited by 184 publications

(151 citation statements)

References 91 publications

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“…2B), is consistent with the observed hyper-and hyporesponsive TCR signals seen in WEDGE and KO mice, respectively. It also concurs with the observation that higher Lck activity favors skewing of T cell differentiation toward CD4 ϩ T cells (28).…”

Section: Discussionsupporting

confidence: 75%

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context. autoimmunity ͉ tyrosine phosphatase ͉ tyrosine kinase ͉ thymocyte development T cell receptor (TCR) signal strength is influenced by the integration of multiple inputs including affinity for antigen, presence and activity of costimulatory molecules, and duration of the interaction with antigen-presenting cells (APCs) (1). Alterations in TCR signal strength impact many aspects of T cell biology including CD4 versus CD8 lineage commitment (1), effector and memory cell generation (2), and autoimmunity (3, 4). Currently, the factors defining signal strength and its functional outcome are incompletely understood.CD45, a receptor-like protein tyrosine phosphatase (RPTP) expressed on all nucleated hematopoietic cells, plays a critical positive regulatory role in antigen receptor signaling. Its absence in both mice and humans results in severe combined immunodeficiency (5, 6). CD45 mediates its effects, at least in part, by modulating the activation state of Src family protein tyrosine kinases (SFKs) (5, 7). Phosphorylation of the SFK C-terminal tyrosine by Csk inhibits the kinase while autophosphorylation of the catalytic domain tyrosine results in full activity. CD45 opposes Csk by dephosphorylating the negative regulatory tyrosine, generating a pool of primed SFKs capable of rapid activation upon receptor stimulation. In some cell types, CD45 can also dephosphorylate the catalytic tyrosine and negatively regulate SFKs.Regulation of CD45 itself is complex. Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initi...

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Section: Discussionsupporting

confidence: 75%

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Nonetheless, some functions have been identified that are unique to Lck. Examples are the positive selection of CD4 single-positive cells and the proliferation of T-cells in lymphopenic environments (46). The significant differences in SH2-SH3 linkage observed here may help to adapt Lck and Fyn to their specific surroundings and to achieve their functional differences.…”

Section: Sh3 and Sh2 Domain Communication By Ligand-bindingmentioning

confidence: 81%

Binding, Domain Orientation, and Dynamics of the Lck SH3−SH2 Domain Pair and Comparison with Other Src-Family Kinases

et al. 2005

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The catalytic activity of Src-family kinases is regulated by association with its SH3 and SH2 domains. Activation requires displacement of intermolecular contacts by SH3/SH2 binding ligands resulting in dissociation of the SH3 and SH2 domains from the kinase domain. To understand the contribution of the SH3-SH2 domain pair to this regulatory process, the binding of peptides derived from physiologically relevant SH2 and SH3 interaction partners was studied for Lck and its relative Fyn by NMR spectroscopy. In contrast to Fyn, activating ligands do not induce communication between SH2 and SH3 domains in Lck. This can be attributed to the particular properties of the Lck SH3-SH2 linker which is shown to be extremely flexible thus effectively decoupling the behavior of the SH3 and SH2 domains. Measurements on the SH32 tandem from Lck further revealed a relative domain orientation that is distinctly different from that found in the Lck SH32 crystal structure and in other Src kinases. These data suggest that flexibility between SH2 and SH3 domains contributes to the adaptation of Src-family kinases to specific environments and distinct functions.

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“…The combinatorial interactions of these paired domains could contribute to differences in the binding specificities and the distinct substrate profile of these SFKs. Specific interactions for either Lck or Fyn have been reported (reviewed in Zamoyska et al, 2003). Distinct localization patterns also may contribute to the distinct specificities of these kinases.…”

Section: Lck and Fyn Domain Structure And Functionmentioning

confidence: 99%

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

2004

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The function of the Src-family kinases (SFKs) Lck and Fyn in T cells has been intensively studied over the past 15 years. Animal models and cell line studies both indicate a critical role for Lck and Fyn in proximal T-cell antigen receptor (TCR) signal transduction. Recruited SFKs phosphorylate TCR ITAMs (immunoreceptor tyrosinebased activation motifs) in the CD3 and f chains, which then serve as docking sites for Syk-family kinases. SFKs then phosphorylate and activate the recruited Syk-family kinase. Lck and Fyn are spatially segregated in cell membranes due to differential lipid raft localization, and may undergo sequential activation. In addition to the CD4 and CD8 coreceptors, a recently described adaptor, Unc119, may link SFKs to the TCR. CD45 and Csk provide positive and negative regulatory control of SFK functions, respectively, and Csk is constitutively bound to the transmembrane adapter protein, PAG/Cbp. TCRbased signaling is required at several stages of T-cell development, including at least pre-TCR signaling, positive selection, peripheral maintenance of naive T cells, and lymphopenia-induced proliferation. SFKs are required for each of these TCR-based signals, and Lck seems to be the major contributor.

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The influence of the src‐family kinases, Lck and Fyn, on T cell differentiation, survival and activation

Cited by 184 publications

References 91 publications

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Binding, Domain Orientation, and Dynamics of the Lck SH3−SH2 Domain Pair and Comparison with Other Src-Family Kinases

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

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