Tyrosine 319 in the Interdomain B of ZAP-70 Is a Binding Site for the Src Homology 2 Domain of Lck

Pelosi, Michele; Bartolo, Vincenzo Di; Mounier, V; Mège, Dominique; Pascussi, Jean‐Marc; Dufour, Evelyne; Blondel, Arnaud; Acuto, Oreste

doi:10.1074/jbc.274.20.14229

Cited by 117 publications

(109 citation statements)

References 46 publications

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“…3A, lanes 1 and 2). One possible explanation is that 3BP2 activates the endogenous Lyn to phosphorylate Tyr 346 in the linker region of Syk, which could bind to the Lyn-SH2 in COS-7 cells because orthologous phosphorylation site in ZAP-70 Tyr 319 is a binding site for the SH2 domain of Lck, a member of Src family PTKs (26,27). However, recent findings revealed that phosphorylation of Tyr 346 is indispensable for Fc⑀RI-mediated mast cell activation (28).…”

Section: Phosphorylation Of Tyr 446 But Not the Sh2 Domain Of 3bp2 Comentioning

confidence: 94%

Adaptor Protein 3BP2 Is a Potential Ligand of Src Homology 2 and 3 Domains of Lyn Protein-tyrosine Kinase

Maeno

Sada

Kyo

et al. 2003

Journal of Biological Chemistry

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Adaptor protein 3BP2 was originally isolated as a proteintyrosine kinase c-Abl-Src homology 3 (SH3) 1 domain-binding protein of unknown function (1). 3BP2 was also identified as a Syk kinase-interacting protein by the yeast two-hybrid screening (2). Transient overexpression of 3BP2 resulted in a transcriptional activation of nuclear factor of activated T cell and activator protein 1, which is induced by T-cell receptor aggregation. Ser 225 and Ser 277 of 3BP2 were identified as essential sites for interacting with 14-3-3 to negatively regulate the function of 3BP2 in lymphocytes (3). Moreover, infection of 3BP2 wild type into NK cells by vaccinia virus enhanced cell cytotoxicity. An in vitro binding study suggested that phosphorylation of Tyr 183 of 3BP2 could be associated with Vav and phospholipase C-␥ (4). In mast cells, overexpression of the 3BP2-SH2 domain suppressed high affinity IgE receptor (Fc⑀RI)-mediated tyrosine phosphorylation of phospholipase C-␥, Ca 2ϩ mobilization, and degranulation (5). These findings have demonstrated that 3BP2 plays a critical role in hematopoietic cells.To propagate the immunoreceptor signal, adaptor proteins contribute to protein-protein and protein-lipid interactions through multiple domains and/or specific phosphotyrosine-containing sequences. Tyrosine phosphorylation of 3BP2 was observed in NK cells and mast cells by cross-linking Fc␥R and Fc⑀RI, respectively (4, 5). To elucidate the function of 3BP2, it is necessary to determine the protein-tyrosine kinase (PTK) that phosphorylates 3BP2 and its binding partner to assemble a signaling complex through specific phosphotyrosine-containing motifs in 3BP2.The Src family PTK Lyn is associated with Fc⑀RI␤. Upon aggregation of Fc⑀RI, Lyn is critical for phosphorylating Fc⑀RI␤ and -␥ subunits on Tyr residues within the immunoreceptor tyrosine-based activating motif (ITAM) (6 -8). By analogy with studies on Hck, Lyn is thought to be activated by the disassembly of the closed intramolecular interaction by (i) CD45-mediated dephosphorylation of C-terminal regulatory Tyr residue, (ii) binding to SH3 and SH2 ligands, and (iii) autophosphorylation of Tyr in the activation loop (9). What is the binding ligand of the SH3 and SH2 domains of Lyn in Fc⑀RI signaling pathway? Pull-down experiments using glutathione S-transferase (GST)-Lyn-SH2 fusion protein indicated that there were multiple phosphoproteins interacting with the Lyn-SH2 after the antigen stimulation of RBL-2H3 cells (10). In addition, although the displacement of intramolecular SH3 interaction is not well understood, it seems likely that some aggregation-induced change in an associated molecule provides a higher affinity SH3 ligand that binds to the Lyn-SH3 domain (11). The SH3 domain is directed toward the proline-rich region, but such a ligand has not been identified yet in the Fc⑀RI signaling.We isolated nonreceptor type PTK Syk from porcine spleen (12). Syk is expressed in hematopoietic, epithelial, and endothelial cells (13)(14)(15)(16). When the ITAM of Fc⑀RI␥ subunits is...

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Section: Phosphorylation Of Tyr 446 But Not the Sh2 Domain Of 3bp2 Comentioning

confidence: 94%

Adaptor Protein 3BP2 Is a Potential Ligand of Src Homology 2 and 3 Domains of Lyn Protein-tyrosine Kinase

Maeno

Sada

Kyo

et al. 2003

Journal of Biological Chemistry

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“…Phosphorylation at this residue acts to enhance the catalytic function of ZAP70, as well as play a scaffolding role within ZAP70 by providing a binding site for LCK and other proteins such as PI3K, Grb2, and CrkII (54,55). The malignant cells from a subset of patients with CLL also express ZAP70 (17) where it functions to enhance BCR signaling (19,20).…”

Section: Discussionmentioning

confidence: 99%

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Talab

Allen

Thompson

et al. 2013

Molecular Cancer Research

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B-cell receptor (BCR) signals promote survival of chronic lymphocytic leukemia (CLL) cells, and it is believed that overexpressed and constitutively active Lyn mediates this signaling. Here, we show that CLL cells express lymphocyte-specific protein tyrosine kinase (LCK) and that inhibition of this Src family tyrosine kinase with the specific inhibitor [4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2-d]pyrimidin-7-yl-cyclopentane (Lck-i)], or reduction of its expression with siRNA, blocks the induction of CD79a, Syk, inhibitor of IkB kinase (IKK), Akt, and extracellular signal-regulated kinase (ERK) phosphorylation by BCR cross-linking in these cells. Furthermore, we show that CLL cells with high levels of LCK expression have higher levels of BCR-mediated IKK, Akt, and ERK phosphorylation as well as cell survival than CLL cells with low levels of LCK expression. We also show that treatment of CLL cells with Lck-i inhibits BCR cross-linking-induced cell survival. Taken together, these data show a major role for LCK in proximal and distal BCR-mediated signaling in CLL cells and suggest that LCK expression is important in the pathogenesis of this disease. On a clinical level, these studies advocate the use of specific LCK inhibitors in the treatment of progressive CLL. Mol Cancer Res; 11(5); 541-54. Ó2013 AACR.

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“…To this aim, we tested ZAP-70 and the adapter protein SLP-76, two key elements required for NF-AT-induced transcriptional activation (48). Similarly to Vav-1, both proteins are tyrosine phosphorylated following TCR ligation (49,50) and when overexpressed in Jurkat cells they cause an increase of basal (40,42) and Fig. 1, A and B, and Fig.…”

Section: Zap-70 or Slp-76 Overexpression Does Not Induce Nf-at Activamentioning

confidence: 99%

“…Rabbit polyclonal antisera were: anti-VSV-G, previously described (40) and anti SLP-76 (M14), directed against a synthetic peptide (from Neosystem SA, Strasbourg, France) corresponding to the first 12 residues of human SLP-76, generated in our laboratory. Sheep polyclonal anti-SLP76 was from Upstate Biotechnology.…”

Section: Abs and Superantigenmentioning

confidence: 99%

CD28 Utilizes Vav-1 to Enhance TCR-Proximal Signaling and NF-AT Activation

Michel

Mangino

Attal-Bonnefoy

et al. 2000

The Journal of Immunology

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The mechanism through which CD28 costimulation potentiates TCR-driven gene expression is still not clearly defined. Vav-1, an exchange factor for Rho GTPases thought to regulate, mainly through Rac-1, various signaling components leading to cytokine gene expression, is tyrosine phosphorylated upon CD28 engagement. Here, we provide evidence for a key role of Vav-1 in CD28-mediated signaling. Overexpression of Vav-1 in Jurkat cells in combination with CD28 ligation strongly reduced the concentration of staphylococcus enterotoxin E/MHC required for TCR-induced NF-AT activation. Surprisingly, upon Vav-1 overexpression CD28 ligation sufficed to activate NF-AT in the absence of TCR engagement. This effect was not mediated by overexpression of ZAP-70 nor of SLP-76 but necessitated the intracellular tail of CD28, the intactness of the TCR-proximal signaling cascade, the Src-homology domain 2 (SH2) domain of Vav-1, and SLP-76 phosphorylation, an event which was favored by Vav-1 itself. Cells overexpressing Vav-1 formed lamellipodia and microspikes reminiscent of Rac-1 and Cdc42 activation, respectively, for which the SH2 domain of Vav-1 was dispensable. Together, these data suggest that CD28 engagement activates Vav-1 to boost TCR signals through a synergistic cooperation between Vav-1 and SLP-76 and probably via cortical actin changes to facilitate the organization of a signaling zone.

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Tyrosine 319 in the Interdomain B of ZAP-70 Is a Binding Site for the Src Homology 2 Domain of Lck

Cited by 117 publications

References 46 publications

Adaptor Protein 3BP2 Is a Potential Ligand of Src Homology 2 and 3 Domains of Lyn Protein-tyrosine Kinase

Adaptor Protein 3BP2 Is a Potential Ligand of Src Homology 2 and 3 Domains of Lyn Protein-tyrosine Kinase

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

CD28 Utilizes Vav-1 to Enhance TCR-Proximal Signaling and NF-AT Activation

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