Abstract
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.
Highlights
The human genetic disorder ataxia-telangiectasia (A-T)1 is characterized by immunodeficiency, neurological abnormality, abnormal development, radiosensitivity, cell cycle anomalies, and cancer predisposition [1,2,3]
Since immunodeficiency is one of the important characteristics of A-T, we have examined signaling through the B cell antigen receptor (BCR)
Expression of Surface Immunoglobulin and Other Molecules on A-T and Normal Lymphoblastoid Cells—In view of the apparent defect in mitogenesis through the BCR, B cell lines derived from A-T patients and controls were initially compared for expression of sIg by immunofluorescence staining
Summary
The human genetic disorder ataxia-telangiectasia (A-T) is characterized by immunodeficiency, neurological abnormality, abnormal development, radiosensitivity, cell cycle anomalies, and cancer predisposition [1,2,3]. The ATM protein is related to TOR1 and TOR2 proteins of yeast [13] and their mammalian counterparts FRAP [14] and RAFT1 [15] through the PI 3-kinase domain, and to a second group of proteins through this domain and through an adjacent region of weaker homology [16] The latter group includes Mei-41 of Drosophila melanogaster, rad3p, Mec1p and Tel1p of yeast, and DNA-dependent protein kinase from human cells [17,18,19,20]. We report here that signaling through the BCR is defective in A-T which is detectable at the level of Ca2ϩ mobilization, PLC␥1 activation, and PI-3 kinase activation These results provide evidence for a role for the ATM protein in intracellular signaling
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