Engagement of the TcR/CD3 complex stimulates p59fyn(T) activity: Detection of associated proteins at 72 and 120–130 kD

Silva, Antonio J. da; Yamamoto, Masahiro; Zalvan, Craig H.; Rudd, Christopher E.

doi:10.1016/0161-5890(92)90215-j

Cited by 56 publications

(36 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5). The pattern fits with the extended kinetics of FYN-T activation following anti-CD3 ligation (53,54). The kinetics also introduces the possibility that FYN-T-FYB-SLP-76 contributes to early and late stages of the T-cell response, possibly contributing to the long term production of IL-2.…”

Section: Discussionmentioning

confidence: 99%

FYN-T-FYB-SLP-76 Interactions Define a T-cell Receptor ζ/CD3-mediated Tyrosine Phosphorylation Pathway That Up-regulates Interleukin 2 Transcription in T-cells

Raab¹,

Kang²,

Silva³

et al. 1999

Journal of Biological Chemistry

Self Cite

128

View full text Add to dashboard Cite

Protein-tyrosine kinases p56Lck , SYK, and ZAP-70 and downstream adaptors LAT and SLP-76 have been implicated as essential components in T-cell activation. Another lymphoid-specific adaptor FYB/SLAP has also been identified as a predominant binding partner of SLP-76 and the Src kinase FYN-T, although its role in the activation process has been unclear. In this study, we demonstrate that FYN-T selectively phosphorylates FYB providing a template for the recruitment of FYN-T and SLP-76 SH2 domain binding. This interaction is unusual in its distinct cytoplasmic localization and its long term stable kinetics of phosphorylation. Furthermore, we demonstrate for the first time that the co-expression of all three components of the FYN-T-FYB-SLP-76 matrix can synergistically up-regulate T-cell receptor-driven interleukin 2 transcription activity. These findings document the existence of a T-cell receptor-regulated FYN-T-FYB pathway that interfaces with the adaptor SLP-76 and up-regulates lymphokine production in T-cells.

show abstract

Section: Discussionmentioning

confidence: 99%

FYN-T-FYB-SLP-76 Interactions Define a T-cell Receptor ζ/CD3-mediated Tyrosine Phosphorylation Pathway That Up-regulates Interleukin 2 Transcription in T-cells

Raab¹,

Kang²,

Silva³

et al. 1999

Journal of Biological Chemistry

Self Cite

128

View full text Add to dashboard Cite

show abstract

“…Unlike the parental Jurkat T cells, this signal seems unlikely to be delivered by Lck in the P116 cells, since Lck does not appear to play an important role in the ZAP-70-independent activation of the Raf-1/MEK-1/Erk cascade, on the basis that Erk could also be activated following CD3 stimulation in the Lck-negative Jurkat T-cell line JCaM1, with a dose dependency and time course similar to those observed in the ZAP-70-negative P116 cells. Fyn would seem to be a logical candidate for providing the requisite Src family signal, since Fyn is also rapidly activated following TCR/CD3 stimulation (12,52) and has been implicated in TCR/CD3-stimulated PLC␥1 activation (1,48,62).…”

Section: Discussionmentioning

confidence: 99%

ZAP-70-Independent Ca²⁺ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation

Shan

Balakir

Criado

et al. 2001

Molecular and Cellular Biology

View full text Add to dashboard Cite

Signals generated on engagement of the T-cell antigen receptor (TCR) are critical in the regulation of T-lymphocyte function. TCR signal transduction is mediated proximally by multiple tyrosine kinases, which act in concert to activate a diverse array of signaling molecules (6,10,35,(55)(56)(57)64). Key among these downstream effectors are the enzymes phospholipase C-␥1 (PLC␥1) and the extracellular-signal-regulated kinase (Erk), both of which need to be activated in order for TCR engagement to result in T cell activation. Activated PLC␥1 catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PI-4,5-P 2 ) to inositol-1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG). The former product regulates the levels of intracellular Ca 2ϩ , while the latter is an activator of the classical (cPKC: ␣, ␤ I , ␤ II and ␥), and novel (nPKC: ␦, ε, and ) isoforms of protein kinase C (PKC) and of Ras-GRP (25). Erk is a proline-directed serine/threonine kinase that can phosphorylate and regulate multiple downstream effectors, including p90 RSK and the transcription factor Elk-1. The nature of the intervening steps between TCR stimulation and activation of these enzymes has begun to be elucidated, but our understanding of this process remains incomplete. Considerable evidence points to a required Lck/Fyncatalyzed tyrosine phosphorylation of the CD3 and TCR chains, with the resultant TCR recruitment and activation of the protein tyrosine kinase (PTK) ZAP-70, which then phosphorylates two of its substrates, SLP-76 and LAT, on key tyrosine residues (10,35,56,57,64). These last two proteins serve as linker molecules. They have no intrinsic enzymatic activity but, when tyrosine phosphorylated, function by appropriately colocalizing other signaling molecules. SLP-76 is cytosolic, while the majority of LAT partitions to the lipid rafts by virtue of posttranslational palmitoylation proximal to the endofacial side of its transmembrane domain. When phosphorylated, LAT binds directly to PLC␥1, Grb2, Grap, and Gads, effectively localizing these molecules and their associated proteins (including phosphatidylinositol 3-kinase, SOS, c-Cbl, Vav, SLP-76, and Itk) to the lipid rafts of the plasma membrane. This event is thought to be required for PLC␥1 tyrosine phosphorylation and activation, as well as the activation of Erk. It has been proposed that the LAT-assembled complex colocalizes PLC␥1 with the activated PTK (possibly Itk) that phosphorylates and activates it and that this process requires 56,64). Additionally, LAT association positions PLC␥1 near its substrate, PI-4,5-P 2 , potentially increasing the rate of PI-4,5-P 2 hydrolysis.Precisely how the formation of the LAT-associated signaling complex leads to Erk activation is unclear. Erk activation proceeds primarily through the sequential activation of Ras, Raf-1, and MEK. It has been suggested that Ras is activated in TCR-stimulated T cells via recruitment of Grb2-associated SOS, a guanine nucleotide exchange factor for Ras, to the

show abstract

“…Of note, the association of Pyk2 with Fyn was similar in both hybridomas (middle panel). Also a p72-kDa phosphoprotein, which normally co-precipitates with and is phosphorylated by Fyn following TCR engagement (31), is absent from Fyn-specific immunoprecipitates from the hybridoma expressing the mutant TCR following SEB presentation (Fig. 3).…”

Section: Phosphorylated Pyk2 In Response To Seb In a T Cell Hybridomamentioning

confidence: 99%

Defective Signaling to Fyn by a T Cell Antigen Receptor Lacking the α-Chain Connecting Peptide Motif

Ulivieri

Peter

Orsini

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

A key role in the communication between the ␣␤TCR and the CD3/ complex is played by a specific motif within the connecting peptide domain of the TCR ␣ chain (␣-CPM). T cell hybridomas expressing an ␣-CPM-mutated TCR show a dramatic impairment in antigen-driven interleukin-2 production. This defect can be complemented by a calcium ionophore, indicating that activation of the calcium pathway is impaired. Several lines of evidence implicate Fyn in the regulation of calcium mobilization, at least in part through the activation of phospholipase C␥. Here we have investigated the potential involvement of Fyn in the TCR ␣-CPM signaling defect. Using T cell hybridomas expressing either a wild-type TCR or an ␣-CPM mutant, we show that Fyn fails to be activated by the mutant receptor following SEB binding and fails to generate tyrosine-phosphorylated Pyk2, a member of the focal adhesion kinase family. This defect correlated with an impairment in phospholipase C␥ phosphorylation. Production of interlukin-2 and activation of the transcription factor NF-AT in response to triggering of the TCR ␣-CPM mutant with SEB were fully restored in the presence of constitutively active Fyn. Hence the signaling defect generated by the TCR ␣-CPM mutation results at least in part from an impaired coupling of the TCR⅐CD3 complex to Fyn activation.

show abstract

Engagement of the TcR/CD3 complex stimulates p59fyn(T) activity: Detection of associated proteins at 72 and 120–130 kD

Cited by 56 publications

References 21 publications

FYN-T-FYB-SLP-76 Interactions Define a T-cell Receptor ζ/CD3-mediated Tyrosine Phosphorylation Pathway That Up-regulates Interleukin 2 Transcription in T-cells

FYN-T-FYB-SLP-76 Interactions Define a T-cell Receptor ζ/CD3-mediated Tyrosine Phosphorylation Pathway That Up-regulates Interleukin 2 Transcription in T-cells

ZAP-70-Independent Ca²⁺ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation

Defective Signaling to Fyn by a T Cell Antigen Receptor Lacking the α-Chain Connecting Peptide Motif

Contact Info

Product

Resources

About

Engagement of the TcR/CD3 complex stimulates p59fyn(T) activity: Detection of associated proteins at 72 and 120–130 kD

Cited by 56 publications

References 21 publications

FYN-T-FYB-SLP-76 Interactions Define a T-cell Receptor ζ/CD3-mediated Tyrosine Phosphorylation Pathway That Up-regulates Interleukin 2 Transcription in T-cells

FYN-T-FYB-SLP-76 Interactions Define a T-cell Receptor ζ/CD3-mediated Tyrosine Phosphorylation Pathway That Up-regulates Interleukin 2 Transcription in T-cells

ZAP-70-Independent Ca2+ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation

Defective Signaling to Fyn by a T Cell Antigen Receptor Lacking the α-Chain Connecting Peptide Motif

Contact Info

Product

Resources

About

ZAP-70-Independent Ca²⁺ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation