Cutting Edge: Functional Role for Proline-Rich Tyrosine Kinase 2 in NK Cell-Mediated Natural Cytotoxicity

Gismondi, Angela; Jacobelli, Jordan; Mainiero, Fabrizio; Paolini, Rossella; Piccoli, Mario; Frati, Luigi; Santoni, Angela

doi:10.4049/jimmunol.164.5.2272

Cited by 51 publications

(56 citation statements)

References 23 publications

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“…In NK cells, LFA-1 has been implicated in a number of signaling processes associated with cytotoxicity. These include granule polarization (5), Vav1 phosphorylation (6), and Pyk2 phosphorylation (7). However, the mechanism by which LFA-1 transduces signals leading to these events remains unclear.…”

Section: N Atural Killer Cells Kill Virus-infected Cells and Tumor Cementioning

confidence: 99%

A Dual Role for Talin in NK Cell Cytotoxicity: Activation of LFA-1-Mediated Cell Adhesion and Polarization of NK Cells

Mace

Monkley

Critchley

et al. 2009

The Journal of Immunology

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LFA-1 is critical for NK cell cytotoxicity because it mediates adhesion of NK cells to target cells. Talin is thought to associate with the cytoplasmic tail of LFA-1 and activates its ligand-binding function. In this study, we report that talin is also required for LFA-1-mediated outside-in signaling leading to NK cell polarization. NK cells generated from talin1-deficient murine embryonic stem cells are defective in LFA-1-mediated adhesion. Although exogenously added manganese activates LFA-1 on talin-deficient NK cells and induces conjugate formation with target cells, their LFA-1-dependent cytotoxicity is impaired. Binding of ICAM-1-coated beads to wild-type NK cells induces reorganization of the actin cytoskeleton and coligation of the activating receptor NKG2D induces polarization of cytotoxic granules, whereas talin1-deficient NK cells fail to polarize with or without NKG2D coligation. Thus, talin1 plays a dual role in NK cell cytotoxicity, first by activation of LFA-1-mediated adhesion and then via LFA-1-induced NK cell polarization.

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Section: N Atural Killer Cells Kill Virus-infected Cells and Tumor Cementioning

confidence: 99%

A Dual Role for Talin in NK Cell Cytotoxicity: Activation of LFA-1-Mediated Cell Adhesion and Polarization of NK Cells

Mace

Monkley

Critchley

et al. 2009

The Journal of Immunology

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“…As both NK and endothelial cells express Pyk-2, we evaluated the tyrosine phosphorylation status of NK cell-derived Pyk-2 by performing binding experiments using unlabeled NK cells and paraformaldehyde-prefixed EAHY endothelial cells as previously reported (19). This treatment prevents a possible activation of kinases expressed by target cells and has no effect on their binding to NK cells.…”

Section: Recombinant Vaccinia Virus Infectionmentioning

confidence: 99%

“…Highly purified (Ն95%) cultured human NK cells were obtained by incubating for 10 days nylon-nonadherent PBMC (4 ϫ 10 5 cells) with irradiated (3000 rad) EBV-transformed B cell line RPMI 8866 (1 ϫ 10 5 cells) as previously described (19). The human endothelial cell line EA.Hy 926 (EAHY) was cultured in DMEM supplemented with 10% FCS and gentamicin (50 g/ml) and in the presence of 100 M hypoxanthine, 0.4 M aminopterin, and 16 M thymidine (30).…”

Section: Cellsmentioning

confidence: 99%

“…Recombinant vaccinia viruses encoding wild-type Pyk-2 or Pyk-M were generated in our laboratory as previously described (19).…”

Section: Recombinant Vaccinia Virus Infectionmentioning

confidence: 99%

“…Engagement of ␤ 1 or ␤ 2 integrins on human NK cells results in the rapid tyrosine phosphorylation of both Pyk-2 and paxillin. Moreover, we found that Pyk-2 acts as an upstream mediator of ␤ 1 and ␤ 2 integrintriggered MAPK cascades and controls the development of NK cell-mediated natural cytotoxicity (18,19).…”

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confidence: 99%

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Proline-Rich Tyrosine Kinase 2 and Rac Activation by Chemokine and Integrin Receptors Controls NK Cell Transendothelial Migration

Gismondi

Jacobelli

Strippoli

et al. 2003

The Journal of Immunology

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Protein tyrosine kinase activation is an important requisite for leukocyte migration. Herein we demonstrate that NK cell binding to endothelium activates proline-rich tyrosine kinase 2 (Pyk-2) and the small GTP binding protein Rac that are coupled to integrin and chemokine receptors. Chemokine-mediated, but not integrin-mediated, Pyk-2 and Rac activation was sensitive to pretreatment of NK cells with pertussis toxin, a pharmacological inhibitor of Gi protein-coupled receptors. Both Pyk-2 and Rac are functionally involved in chemokine-induced NK cell migration through endothelium or ICAM-1 or VCAM-1 adhesive proteins, as shown by the use of recombinant vaccinia viruses encoding dominant negative mutants of Pyk-2 and Rac. Moreover, we found that Pyk-2 is associated with the Rac guanine nucleotide exchange factor Vav, which undergoes tyrosine phosphorylation upon integrin triggering. Finally, we provide direct evidence for the involvement of Pyk-2 in the control of both chemokine- and integrin-mediated Rac activation. Collectively, our results indicate that Pyk-2 acts as a receptor-proximal link between integrin and chemokine receptor signaling, and the Pyk-2/Rac pathway plays a pivotal role in the control of NK cell transendothelial migration.

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NKG2D engagement on human NK cells leads to DNAM‐1 hypo‐responsiveness through different converging mechanisms

et al. 2022

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Natural killer (NK) cell activation is regulated by activating and inhibitory receptors that facilitate diseased cell recognition. Among activating receptors, NKG2D and DNAM-1 play a pivotal role in anticancer immune responses since they bind ligands upregulated on transformed cells. During tumor progression, however, these receptors are frequently downmodulated and rendered functionally inactive. Of note, NKG2D internalization has been associated with the acquisition of a dysfunctional phenotype characterized by the cross-tolerization of unrelated activating receptors. However, our knowledge of the consequences of NKG2D engagement is still incomplete. Here, by cytotoxicity assays combined with confocal microscopy, we demonstrate that NKG2D engagement on human NK cells impairs DNAM-1-mediated killing through two different converging mechanisms: by the upregulation of the checkpoint inhibitory receptor TIGIT, that in turn suppresses DNAM-1-mediated cytotoxic function, and by direct inhibition of DNAM-1-promoted signaling. Our results highlight a novel interplay between NKG2D and DNAM-1/TIGIT receptors that may facilitate neoplastic cell evasion from NK cell-mediated clearance.

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Cutting Edge: Functional Role for Proline-Rich Tyrosine Kinase 2 in NK Cell-Mediated Natural Cytotoxicity

Cited by 51 publications

References 23 publications

A Dual Role for Talin in NK Cell Cytotoxicity: Activation of LFA-1-Mediated Cell Adhesion and Polarization of NK Cells

A Dual Role for Talin in NK Cell Cytotoxicity: Activation of LFA-1-Mediated Cell Adhesion and Polarization of NK Cells

Proline-Rich Tyrosine Kinase 2 and Rac Activation by Chemokine and Integrin Receptors Controls NK Cell Transendothelial Migration

NKG2D engagement on human NK cells leads to DNAM‐1 hypo‐responsiveness through different converging mechanisms

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