A role for protein tyrosine kinase activity in natural cytotoxicity as well as antibody-dependent cellular cytotoxicity. Effects of herbimycin A.
NK cells, CD3- large granular lymphocytes, have diverse means by which they lyse targets, including antibody-dependent cellular cytotoxicity. The low affinity receptor for the Fc portion of Ig (Fc gamma RIIIA), like the TCR, is a multimeric receptor complex coupled to a protein tyrosine kinase. In the present study, we observed that inhibition of tyrosine kinase activity by herbimycin A interferes with receptor-mediated phosphorylation of a variety of substrates and mobilization of intracellular calcium. Fc gamma RIIIA induced IL-2R alpha-chain expression was also extremely sensitive to herbimycin A as was antibody-dependent cellular cytotoxicity, in fact more so than receptor-mediated phosphorylation and calcium mobilization. In contrast to Fc gamma RIIIA, the surface molecules and biochemical mechanisms involved in NK cytotoxicity and lymphokine-activated killing are not well characterized. Interestingly, however, herbimycin A also blocks these modes of cytolysis, implicating a role for tyrosine kinase function in these processes. Whether FcR-mediated signaling and receptor-mediated signaling involved in NK activity share specific biochemical intermediates is not known, but the involvement of tyrosine kinase function in the latter means of cytotoxicity may provide novel avenues for understanding the biochemical basis of this perplexing cellular function.
O'Shea
J J
JJ
Leukocyte Cell Biology Section, Program Resources, Inc./DynCorp, National Cancer Institute, Frederick, MD 21702-1201.
McVicar
D W
DW
Kuhns
D B
DB
Ortaldo
J R
JR
D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000943:Antigens, Differentiation / Q000502:physiology; D016227:Benzoquinones; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects; D047029:Lactams, Macrocyclic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology*; D011961:Receptors, Fc / Q000502:physiology; D017452:Receptors, IgG; D015375:Receptors, Interleukin-2 / Q000032:analysis; D017828:Rifabutin / Q000031:analogs & derivatives
D000943:Antigens, Differentiation; D016227:Benzoquinones; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; D011809:Quinones; D011961:Receptors, Fc; D017452:Receptors, IgG; D015375:Receptors, Interleukin-2; D017828:Rifabutin; C020754:herbimycin; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases