Physical and functional association of Fc mu receptor on human natural killer cells with the zeta- and Fc epsilon RI gamma-chains and with src family protein tyrosine kinases.
We recently reported that Fc mu R on NK cells is a signal transducing protein that stimulates a rapid increase in the level of cytoplasmic free calcium upon binding of IgM. This study was designed to examine signal transduction via the Fc mu R on NK cells and to characterize intracellular second messengers activated by IgM. Immunoprecipitation of IgM-bound Fc mu R by IgM-specific Ab coimmunoprecipitated the zeta- and Fc epsilon RI gamma-chains. Furthermore, engagement and clustering of Fc mu R by polyclonal IgM induced tyrosine phosphorylation of the zeta- and Fc epsilon RI gamma-chains, indicating their functional association with the Fc mu R-induced signal transduction cascade. Ligand-induced clustering of the Fc mu R also induced activity of src family kinases, Lck, Fyn, Lyn, and Src, as well as their physical interaction with the receptor. Triggering via Fc mu R also induced the activity of Syk and Zap-70, tyrosine kinases demonstrated to associate with zeta and Lck. Phospholipase C-gamma 1 and phosphatidylinositol 3-kinase were identified as substrates phosphorylated on tyrosine, as down-stream components of the signaling pathway activated in NK cells by polyclonal IgM. Although the Fc mu R on NK cells has not yet been biochemically characterized, our results suggest that the zeta- and Fc epsilon RI gamma-chains are functional subunits of this as well as other important cell surface receptors and that the Fc mu R is coupled either directly or indirectly to nonreceptor tyrosine kinases, which phosphorylate and thereby activate regulatory enzymes such as phospholipase C-gamma 1 and phosphatidylinositol 3-kinase.
Rabinowich
H
H
Department of Pathology and Medicine, University of Pittsburgh School of Medicine, PA, USA.
Manciulea
M
M
Metes
D
D
Sulica
A
A
Herberman
R B
RB
Corey
S J
SJ
Whiteside
T L
TL
D002118:Calcium / Q000502:physiology*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000502:physiology; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D007152:Immunologic Capping; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000502:physiology; D007694:Killer Cells, Natural / Q000737:chemistry / Q000502:physiology*; D005810:Multigene Family; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000145:classification / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology; D011961:Receptors, Fc / Q000737:chemistry / Q000502:physiology*; D017455:Receptors, IgE / Q000737:chemistry / Q000502:physiology*; D015290:Second Messenger Systems; D000072377:Syk Kinase; D010738:Type C Phospholipases / Q000502:physiology; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases / Q000502:physiology
D004792:Enzyme Precursors; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D011961:Receptors, Fc; D017455:Receptors, IgE; C035311:immunoglobulin M receptor; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D016392:Proto-Oncogene Proteins pp60(c-src); C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium