Structural requirements for enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck.

Caron, Lorraine; Abraham, Ninan; Pawson, Tony; Veillette, André

doi:10.1128/mcb.12.6.2720

Cited by 92 publications

(53 citation statements)

References 47 publications

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“…Ag-independent T cell SFK activation by DCs has been observed previously (36), but the functional consequences for T cell activation remained unclear. In this study, we show that Ag-independent DC-mediated SFK activation does not result in full TCR activation, as T cells fail to undergo substantial phosphorylation of CD3 or TCR down-modulation (37) (Fig. 2A).…”

Section: Discussionmentioning

confidence: 68%

“…Moreover, an up-regulated serial TCR triggering capacity of DCs is equally unlikely. This reasoning is evidenced by the fact that Lck activation results in enhanced TCR signaling in response to TCR agonists that are fully incapable of serial triggering (37,38). Thus, it follows that up-regulation of the serial TCR triggering rate is unlikely the mechanistic reason for superior T cell stimulation by SFK-mediated TCR licensing.…”

Section: Discussionmentioning

confidence: 99%

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Dendritic Cells Sensitize TCRs through Self-MHC-Mediated Src Family Kinase Activation

Meraner

Hořejšı́

Wölpl

et al. 2007

The Journal of Immunology

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It is unclear whether peptide-MHC class II (pMHC) complexes on distinct types of APCs differ in their capacity to trigger TCRs. In this study, we show that individual cognate pMHC complexes displayed by dendritic cells (DCs), as compared with nonprofessional APCs, are far better in productively triggering Ag-specific TCRs independently of conventional costimulation. As we further show, this is accomplished by the unique ability of DCs to robustly activate the Src family kinases (SFKs) Lck and Fyn in T cells even in the absence of cognate peptide. Instead, this form of SFK activation depends on interactions of DC-displayed MHC with TCRs of appropriate restriction, suggesting a central role of self-pMHC recognition. DC-mediated SFK activation leads to “TCR licensing,” a process that dramatically increases sensitivity and magnitude of the TCR response to cognate pMHC. Thus, TCR licensing, besides costimulation, is a main mechanism of DCs to present Ag effectively.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Dendritic Cells Sensitize TCRs through Self-MHC-Mediated Src Family Kinase Activation

Meraner

Hořejšı́

Wölpl

et al. 2007

The Journal of Immunology

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“…Mutation of Tyr-394 to phenylalanine not only decreases Lck activity in unstimulated cells, but also prevents activation of Lck by oxidative stress. In addition, Lck that has been genetically activated by mutation of Tyr-505 to phenylalanine loses its transforming ability when Tyr-394 is also mutated to phenylalanine (21,40). We previously showed that the extent of Tyr-505 phosphorylation in Lck from H 2 O 2 -stimulated cells was at least as great as that of Tyr-394.…”

Section: Discussionmentioning

confidence: 99%

The Activated Form of the Lck Tyrosine Protein Kinase in Cells Exposed to Hydrogen Peroxide Is Phosphorylated at Both Tyr-394 and Tyr-505

Hardwick

Sefton

1997

Journal of Biological Chemistry

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Members of the Src family of non-receptor tyrosine protein kinases are known to be inhibited by the intramolecular association between a phosphorylated carboxyl-terminal tyrosine residue and the SH2 domain. We have previously shown that exposure of cells to H 2 O 2 strongly activates Lck, a lymphocyte-specific Src family kinase, by inducing phosphorylation on Tyr-394, an absolutely conserved residue within the activation loop of the catalytic domain. Here we show that Lck that has been activated by H 2 O 2 is simultaneously phosphorylated at both the carboxyl-terminal tyrosine (Tyr-505) and Tyr-394. Thus, dephosphorylation of Tyr-505 is not a prerequisite for either phosphorylation of Lck at Tyr-394 or catalytic activation of the kinase. These results indicate that activation of Lck by phosphorylation of Tyr-394 is dominant over any inhibition induced by phosphorylation of Tyr-505. We propose that these results may be extended to all Src family members.p56 lck , a member of the Src family of non-receptor tyrosine protein kinases (1, 2), is expressed predominantly in T cells. Lck function is critical both for T-cell development in the thymus (3, 4) and activation of mature T cells in the periphery by antigen (5, 6). Lck stably associates with the inner surface of the plasma membrane as a result of myristoylation of Gly-2 and palmitoylation of Ser-3 and Ser-5 (7-10). There it binds to the T-cell receptor-associated glycoproteins CD4 and CD8 as well as other proteins through its unique amino terminus (11-15). The activity of Lck is regulated by phosphorylation of two conserved tyrosine residues. Tyr-505 (equivalent to Tyr-527 in c-Src) is located near the carboxyl terminus of Lck and, when phosphorylated, associates intramolecularly with the SH2 domain in the amino-terminal half of the protein. This helps stabilize Lck in a conformation that, biologically, is relatively inactive (16 -20). In the absence of phosphorylation at Tyr-505, intramolecular binding of the carboxyl terminus to the SH2 domain does not occur, and Lck exhibits increased activity in vivo. In contrast, phosphorylation of Tyr-394 (equivalent to Tyr-416 in c-Src) stimulates the catalytic activity of Lck (21-23). Phosphorylation of Tyr-394 allows the formation of hydrogen bonds between the phosphate of Tyr(P) 1 -394 and amino acid residues in the catalytic cleft. These interactions allow the enzyme to assume a conformation resembling that of activated cyclic AMP-dependent protein kinase A (19, 20, 24 -26).We have previously demonstrated that hydrogen peroxide, a potent activator of Lck, acts by inducing phosphorylation of Lck on 37). It is likely that the effects of exposing cells to H 2 O 2 are mediated by global inhibition of tyrosine phosphatases (27-31). The increase in phosphorylation of Lck at Tyr-394 that we observe in the presence of H 2 O 2 may therefore result largely from reduced dephosphorylation of this site. Our previous work did not address the question of whether or not activation of Lck by H 2 O 2 -induced phosphorylation of Tyr-394...

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“…The results using A2 and A6 Lck mutants in this study indicated a preferential role of myristoylation for membrane localization of Lck. Earlier study demonstrated the importance of myristoylation at glysine 2 of Lck in T cell function (27). Recently, Kabouridis et al (28) reported that palmitoylation of Lck at cysteine 3 and 5 is essential for its signaling function in T cells.…”

Section: Discussionmentioning

confidence: 99%

Serine 6 of Lck Tyrosine Kinase: A Critical Site for Lck Myristoylation, Membrane Localization, and Function in T Lymphocytes

Yasuda¹,

Kosugi

Hayashi

et al. 2000

The Journal of Immunology

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Lck is a member of the Src family kinases expressed predominantly in T cells, and plays a pivotal role in TCR-mediated signal transduction. Myristoylation of glysine 2 in the N-terminal Src homology 4 (SH4) domain of Lck is essential for membrane localization and function. In this study, we examined a site within the SH4 domain of Lck regulating myristoylation, membrane localization, and function of Lck. A Lck mutant in which serine 6 (Ser6) was substituted by an alanine was almost completely cytosolic in COS-7 cells, and this change of localization was associated with a drastic inhibition of myristoylation in this mutant. To assess the role of Ser6 of Lck in T cell function, we established stable transfectants expressing various Lck mutants using Lck-negative JCaM1 cells. The Lck mutant of Ser6 to alanine, most of which did not target to the plasma membrane, was not able to reconstitute TCR-mediated signaling events in JCaM1 cells, as analyzed by tyrosine phosphorylation of intracellular proteins and CD69 expression. These results demonstrate that Ser6 is a critical factor for Lck myristoylation, membrane localization, and function in T cells, presumably because the residue is important for N-myristoyl transferase recognition.

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Structural requirements for enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck.

Cited by 92 publications

References 47 publications

Dendritic Cells Sensitize TCRs through Self-MHC-Mediated Src Family Kinase Activation

Dendritic Cells Sensitize TCRs through Self-MHC-Mediated Src Family Kinase Activation

The Activated Form of the Lck Tyrosine Protein Kinase in Cells Exposed to Hydrogen Peroxide Is Phosphorylated at Both Tyr-394 and Tyr-505

Serine 6 of Lck Tyrosine Kinase: A Critical Site for Lck Myristoylation, Membrane Localization, and Function in T Lymphocytes

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