Regulation of NK Cell-Mediated Cytotoxicity by the Adaptor Protein 3BP2

Jevremović, Dragan; Billadeau, Daniel D.; Schoon, Renée A.; Dick, Chris; Leibson, Paul J.

doi:10.4049/jimmunol.166.12.7219

Cited by 63 publications

(93 citation statements)

References 49 publications

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“…Full-length Itk containing an EE-epitope tag was subcloned into the pSP11 vector as described previously (18). A point mutation in the Itk kinase domain (K391R), which prevents ATP binding and thereby Itk activation, was generated with the QuikChange Site-Directed Mutagenesis kit (Stratagene) in accordance with the manufacturer's instructions.…”

Section: Recombinant Vacciniamentioning

confidence: 99%

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Khurana

Arneson

Schoon

et al. 2007

The Journal of Immunology

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NK cells are effector lymphocytes that can recognize and eliminate virally infected and transformed cells. NK cells express distinct activating receptors, including an ITAM-containing FcR complex that recognizes Ab-coated targets, and the DNAX-activating protein of 10 kDa-containing NKG2D receptor complex that recognizes stress-induced ligands. The regulatory role of specific tyrosine kinases in these pathways is incompletely understood. In this study, we show that, in activated human NK cells, the tyrosine kinase IL-2-inducible T cell kinase (Itk), differentially regulates distinct NK-activating receptors. Enhanced expression of Itk leads to increases in calcium mobilization, granule release, and cytotoxicity upon stimulation of the ITAM-containing FcR, suggesting that Itk positively regulates FcR-initiated cytotoxicity. In contrast, enhanced Itk expression decreases cytotoxicity and granule release downstream of the DNAX-activating protein of 10 kDa-containing NKG2D receptor, suggesting that Itk is involved in a pathway of negative regulation of NKG2D-initiated granule-mediated killing. Using a kinase mutant, we show that the catalytic activity of Itk is required for both the positive and negative regulation of these pathways. Complementary experiments where Itk expression was suppressed also showed differential regulation of the two pathways. These findings suggest that Itk plays a complex role in regulating the functions initiated by distinct NK cell-activating receptors. Moreover, understanding how these pathways may be differentially regulated has relevance in the setting of autoimmune diseases and antitumor immune responses where NK cells play key regulatory roles.

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Section: Recombinant Vacciniamentioning

confidence: 99%

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Khurana

Arneson

Schoon

et al. 2007

The Journal of Immunology

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“…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.…”

mentioning

confidence: 99%

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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“…Cependant, les données publiées, fondées sur des approches de type gain ou perte de fonction, indiquent que 3BP2 joue un rôle régulateur dans la signalisation des immunorécepteurs dépendante des kinases Src et Syk (Figure 2). Ainsi, 3BP2 a été impliquée dans la stimulation par le récepteur FcγRIII de la cytotoxicité des cellules NK [11], la dégranulation induite par l'aggrégation des récepteurs FcεRI [10], ou encore l'activation, par les récepteurs de l'antigène de cellules T (TCR) et B (BCR), de NFAT et AP-1, deux facteurs transcriptionnels essentiels à l'homéostasie des leucocytes [4,12]. Dans ce contexte, une fonction probable de 3BP2 est à rechercher dans une cascade de signalisation dépen-dante de la PLC-γ, régulant le métabolisme lipidique et calcique des leucocytes stimulés par les immunoré-cepteurs.…”

Section: Bp2 : Structure Et Partenaires Moléculairesunclassified

“…Le domaine SH2 de 3BP2 peut également se lier au motif YEN présent dans la partie intracytoplasmique de l'adapteur transmembranaire LAT exprimé par les cellules T et NK [4,10] [7,12]. Le résidu phospho-Tyr183 repré-sente un site de fixation du domaine SH2 de Vav1 [11], alors que le résidu phophoTyr446 interagit avec les domaines SH2 de Lyn et Lck [7,12]. L'importance de ces événements est illustrée par le fait que la surexpression de formes mutées de 3BP2 sur les résidus Tyr183 ou Tyr446 réduit la signalisation par 3BP2 dans les cellules T ( [12] et Deckert, résultats non publiés) et NK [11].…”

unclassified

“…Le résidu phospho-Tyr183 repré-sente un site de fixation du domaine SH2 de Vav1 [11], alors que le résidu phophoTyr446 interagit avec les domaines SH2 de Lyn et Lck [7,12]. L'importance de ces événements est illustrée par le fait que la surexpression de formes mutées de 3BP2 sur les résidus Tyr183 ou Tyr446 réduit la signalisation par 3BP2 dans les cellules T ( [12] et Deckert, résultats non publiés) et NK [11]. À l'inverse, et bien que 3BP2 interagisse avec Abl, on ne sait encore si trices est une preuve supplémentaire de l'importance de ces protéines dans la signalisation cellulaire.…”

unclassified

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L’adaptateur 3BP2

Deckert

2006

Med Sci (Paris)

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Regulation of NK Cell-Mediated Cytotoxicity by the Adaptor Protein 3BP2

Cited by 63 publications

References 49 publications

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

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

L’adaptateur 3BP2

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