Defective signaling through the B cell antigen receptor in Epstein-Barr virus-transformed ataxia-telangiectasia cells.
A characteristic series of immunological abnormalities are observed in the human genetic disorder ataxia-telangiectasia (A-T). The recent cloning of a gene mutated in this syndrome provides additional evidence for a defect in intracellular signaling in A-T. We have investigated the possibility that signaling through the B cell antigen receptor is one manifestation of the A-T defect. In response to cross-linking of the B cell receptor, several A-T cell lines were defective in their mitogenic response; in addition Ca2+ mobilization from internal stores was either absent or considerably reduced in these cell lines in response to cross-linking. The defect in signaling was not due to difference in expression of surface immunoglobulin. The defective response in A-T cells was also evident in several arms of the intracellular cascade activated by B cell cross-linking. Tyrosine phosphorylation of phospholipase Cgamma1, a key step in activation of the enzyme, was reduced or negligible in some A-T cell lines. This defect in signaling was also seen at the level of Lyn tyrosine kinase activation and its association with and activation of phosphatidylinositol 3-kinase. Our results provide evidence for a role for the ATM gene product in intracellular signaling which may account at least in part for the abnormalities in B cell function in A-T.
Khanna
K K
KK
Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, P.O. Royal Brisbane Hospital, Herston, Brisbane 4029, Australia. KumkumK@qimr.edu.au
Yan
J
J
Watters
D
D
Hobson
K
K
Beamish
H
H
Spring
K
K
Shiloh
Y
Y
Gatti
R A
RA
Lavin
M F
MF
D001260:Ataxia Telangiectasia / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002472:Cell Transformation, Viral; D004854:Herpesvirus 4, Human; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology*; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D007527:Isoenzymes; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium