Defective Signaling through the B Cell Antigen Receptor in Epstein-Barr Virus-transformed Ataxia-Telangiectasia Cells

• Published in: The Journal of biological chemistry 1997-04, Vol.272 (14), p.9489-9495
• Main Authors: Khanna, K K, Yan, J, Watters, D, Hobson, K, Beamish, H, Spring, K, Shiloh, Y, Gatti, R A, Lavin, M F
• Format: Article
• Language: English
• Subjects: Ataxia Telangiectasia - physiopathology; Calcium - metabolism; Cell Division; Cell Line; Cell Transformation, Viral; Herpesvirus 4, Human; Humans; Isoenzymes - metabolism; Phosphatidylinositol 3-Kinases; Phospholipase C gamma; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Receptors, Antigen, B-Cell - metabolism; Receptors, Antigen, B-Cell - physiology; Receptors, IgG - metabolism; Signal Transduction; Type C Phospholipases - metabolism; Tyrosine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.14.9489

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 Ca 2+ 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 Cγ1, 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.