A p56 -independent Pathway of CD2 Signaling Involves Jun Kinase

Sunder‐Plaßmann, Raute; Reinherz, Ellis L.

doi:10.1074/jbc.273.37.24249

Cited by 24 publications

(21 citation statements)

References 89 publications

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“…ZAP-70 is essential for Ca 2ϩ influx, persistent phosphorylation of , cytokine production, and proliferation. This is consistent with earlier observations showing that CD2-mediated activation of T cells requires expression of the -chain (14,15) and induces phosphorylation (8) and ZAP-70 tyrosine phosphorylation in Jurkat T cells, although to a lesser extent than activation through the TCR (13). Our finding that ZAP-70 is essential for CD2-mediated persistent phosphorylation of in human mature T cells is consistent with a previous report showing that CD3 activation does not induce phosphorylation in another ZAP-70-deficient model, the P116 Jurkat T cell clone (31).…”

Section: Discussionsupporting

confidence: 81%

“…It has been demonstrated that CD2-mediated signaling can occur independently of the ITAMs of the -chain (18). CD2 activation of the JCAM1.6 clone of Jurkat leukemia cells, which lacks Lck expression, can activate the c-Jun N-terminal kinase involved in IL-2 regulation of transcription (13). CD3-mediated activation of these cells induces neither c-Jun N-terminal kinase activation nor IL-2 transcription (13).…”

Section: Discussionmentioning

confidence: 99%

“…In some studies, stimulation via CD2 or CD3 induced tyrosine phosphorylation of indistinguishable patterns of polypeptides (10). Despite these similarities, a number of differences between these two pathways have also been described (11)(12)(13).…”

mentioning

confidence: 99%

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Differential Requirement of ZAP-70 for CD2-Mediated Activation Pathways of Mature Human T Cells

Meinl

Lengenfelder

Blank

et al. 2000

The Journal of Immunology

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This study addresses the role of the tyrosine kinase ZAP-70 in CD2-mediated T cell activation. Patients lacking ZAP-70 have few mature CD8+ T cells and high numbers of CD4+ T cells that are nonfunctional upon TCR triggering. Such a patient with a homozygous deletion in the zap-70 gene that resulted in the complete absence of ZAP-70 protein expression has been identified. Expression of the tyrosine kinases Lck, Fyn, and Syk was normal. The patient’s T cells were activated with two different pairs of mitogenic mAbs. CD2-induced phosphorylation of the ζ-chain and influx of Ca2+ was defective in the ZAP-70-deficient T cells, whereas CD2-induced phosphorylation of several other proteins, including Syk, was not affected. CD2-induced proliferation as well as production of TNF-α and IFN-γ was abrogated in ZAP-70-deficient T cells, whereas PMA plus ionomycin induced normal activation of these cells. Together, this study shows that CD2-activation triggers ZAP-70-dependent and -independent pathways. Deletion of ZAP-70 affected CD2- and CD3-mediated proliferation and cytokine production in a similar way, suggesting that one of the different CD2 pathways converges with a CD3 pathway at or upstream of the activation of ZAP-70.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Differential Requirement of ZAP-70 for CD2-Mediated Activation Pathways of Mature Human T Cells

Meinl

Lengenfelder

Blank

et al. 2000

The Journal of Immunology

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“…Tyrosine 402 of Pyk2 is critical for its function, probably through formation of a Pyk2-Fyn complex leading to the activation of Rac1-JNK pathway followed by the production of IL-2. Recent findings suggest that Pyk2 may function downstream of LFA-1 (39) and of CD2 (40). As LFA-1 and CD2 are critical for the formation of immunological synapse (41), Pyk2 might function in forming or sustaining it for full activation of the T cells.…”

Section: Discussionmentioning

confidence: 99%

Protein-tyrosine Kinase Pyk2 Is Involved in Interleukin-2 Production by Jurkat T Cells via Its Tyrosine 402

Katagiri¹,

Takahashi²,

Sasaki³

et al. 2000

Journal of Biological Chemistry

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We established Jurkat transfectants that overexpress Pyk2 or its mutants, K457A (lysine 457 was mutated to alanine), Pyk2-Y402F (tyrosine 402 to phenylalanine), and Pyk2-Y881F to investigate the role of Pyk2 in T cell activation. Pyk2 as well as kinase-inactive Pyk2-K457A, was phosphorylated at tyrosine residues 402, 580, and 881 upon T cell antigen receptor cross-linking, indicating that these residues are phosphorylated by other tyrosine kinase(s). However, no tyrosine phosphorylation of Pyk2-Y402F was detected while more than 60% of the tyrosine phosphorylation was observed in Pyk2-Y881F. Pyk2-Y402F inhibited the activation of endogenous Pyk2. The degree of activation of both c-Jun NH 2 -terminal kinase and p38 mitogen-activated protein kinase but not extracellular signal-regulated protein kinase after concurrent ligation of T cell antigen receptor and CD28 was reduced by more than 50% in the clones expressing Pyk2-Y402F. Consistent with this inhibition, IL-2 production was significantly diminished in the Pyk2-Y402F-expressing clones. Furthermore, we found that Pyk2, when overexpressed, associates with Zap70 and Vav. Taken together, these findings suggest that Pyk2 is involved in the activation of T cells through its tyrosine 402. Engagement of T cell antigen receptor (TCR)1 by antigen or ligation of TCR by anti-CD3 Ab rapidly activates the Src family protein-tyrosine kinases (PTKs), Fyn and Lck, leading to the phosphorylation of the immunoreceptor tyrosine-based activation motifs in the CD3 complex (1). Phosphorylated immunoreceptor tyrosine-based activation motifs interact with the Src homology (SH) 2 domains of the Syk/Zap70 family PTKs, resulting in the activation of these PTKs, and in turn, in the phosphorylation of an array of cellular proteins (1). Phospholipase C-␥1, phosphatidylinositol 3-kinase, Ras GTPase-activating protein, Vav, Slp76, and LAT (linker for activation of T cells) are tyrosine-phosphorylated early in the activation of the T cells. However, these signals are not sufficient, and additional signals provided by the occupancy of auxiliary receptors (co-receptors), such as CD28, by ligands on the surface of the antigen-presenting cells are necessary (2). Engagement of these receptors triggers pathways that are integrated to induce transcription of the gene for interleukin-2 (IL-2), a major T cell growth factor. Absence of costimulation leads to an anergic state in which T cells lose the ability to induce IL-2 upon restimulation. Production of IL-2 by T cells requires activation of three distinct mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK), c-Jun NH 2 -terminal kinase (JNK) and p38 MAP kinase (3-5). In T cells, JNK and p38 MAP kinase are synergistically activated by costimulation of the TCR/CD3 and CD28 receptors, while no synergy is observed in the ERK activation (4, 5). Although these MAP kinases are supposed to be regulated by different PTKs and small GTPases (6), the more precise mechanisms for the activation of these MAP kinases, especially of J...

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“…However, unlike TCR␣␤, the pre-TCR has an additionally extended cytoplasmic tail encoded by the pT␣ gene. Within the tail two proline-rich motifs can be identified by sequence similarity to motifs in the cytoplasmic tail of human CD2 that mediate binding to CD2BP2, an adaptor molecule involved in intracellular signaling (8,16). Heretofore, the importance of the intracytoplasmic region of the pre-TCR has been uncertain, but very recently the expression of pT␣ mutants in retrovirally transduced T cell precursors and cell lines showed that the pT␣ cytoplasmic tail, in particular the proline-rich domain, plays a crucial role in pre-TCR signal transduction (17).…”

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confidence: 99%

Molecular Mechanisms of Pre-T Cell Receptor-induced Survival

Murga

Barber

2002

Journal of Biological Chemistry

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En route to maturing as T cell receptor (TCR) ␣␤-expressing cells, the development of thymocytes is contingent on expression of a pre-TCR complex comprising a TCR␤ chain paired with a surrogate TCR␣ chain, pre-T␣ (pT␣). The pre-TCR has been proposed to promote cell survival, proliferation, differentiation, and lineage commitment. However, the precise molecular mechanisms governing this variety of effects remain elusive. Here, we present a cellular system designed to biochemically dissect signals elicited upon pre-TCR expression. Using the T cell line 4G4 stably transfected with one of the two known pT␣ isoforms or selective pT␣ deletion mutants and TCR␤, we were able to observe that expression of a functional pre-TCR complex is sufficient to control the levels of surface Fas protein, the stimulation of mitogen-activated and stress-regulated kinases, and the activation status of the p53 antioncogene. We demonstrate that this regulation has a major impact on the expression of important regulators of apoptosis, such as Bcl-2 family members, and the cell cycle, such as p21 WAF . Furthermore, we show here that cells expressing a functional pre-TCR are more resistant to different types of DNA damage-induced apoptosis and that these effects are contingent on an intact cytoplasmic tail of pT␣. We finally propose that the presence of a functional pre-TCR complex triggers many intracellular pathways capable of driving and ensuring thymocyte survival in the presence of DNA damage.

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A p56 -independent Pathway of CD2 Signaling Involves Jun Kinase

Cited by 24 publications

References 89 publications

Differential Requirement of ZAP-70 for CD2-Mediated Activation Pathways of Mature Human T Cells

Differential Requirement of ZAP-70 for CD2-Mediated Activation Pathways of Mature Human T Cells

Protein-tyrosine Kinase Pyk2 Is Involved in Interleukin-2 Production by Jurkat T Cells via Its Tyrosine 402

Molecular Mechanisms of Pre-T Cell Receptor-induced Survival

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