Regulation of NK cell-mediated cytotoxicity by the adaptor protein 3BP2.
Stimulation of lymphocytes through multichain immune recognition receptors activates multiple signaling pathways. Adaptor proteins play an important role in integrating these pathways by their ability to simultaneously bind multiple signaling components. Recently, the 3BP2 adaptor protein has been shown to positively regulate the transcriptional activity of T cells. However, the mechanisms by which signaling components are involved in this regulation remain unclear, as does a potential role for 3BP2 in the regulation of other cellular functions. Here we describe a positive regulatory role for 3BP2 in NK cell-mediated cytotoxicity. We also identify p95(vav) and phospholipase C-gamma isoforms as binding partners of 3BP2. Our results show that tyrosine-183 of 3BP2 is specifically involved in this interaction and that this residue critically influences 3BP2-dependent function. Therefore, 3BP2 regulates NK cell-mediated cytotoxicity by mobilizing key downstream signaling effectors.
Jevremovic
D
D
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Billadeau
D D
DD
Schoon
R A
RA
Dick
C J
CJ
Leibson
P J
PJ
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins; D003602:Cytotoxicity, Immunologic; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019169:Jurkat Cells; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism / Q000502:physiology; D051746:ZAP-70 Protein-Tyrosine Kinase; D018909:src Homology Domains / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D007527:Isoenzymes; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG; D011971:Receptors, Immunologic; C496618:VAV1 protein, human; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D010738:Type C Phospholipases; D051966:Phospholipase C gamma