Molecular and Cellular Aspects of X-Linked Agammaglobulinemia

The activation loop in Lck regulates oncogenic potential by inhibiting basal kinase activity and restricting substrate specificity

“…The structural analysis studies of kinases in complex with inhibitor peptides suggest that this region may also be important for substrate selection (Hubbard, 1997;Madhusudan et al, 1994;Zheng et al, 1993). Several naturally occurring activation loop mutations in the Ret receptor (Hofstra et al, 1994) and Btk (Sideras and Smith, 1995) tyrosine kinases aect activation while mutation at a dierent residue in the Kit receptor alters substrate selection (Piao et al, 1996). Substitution of the loop in Lck with a homologous domain from the Ser/Thr kinase c-raf decreased autophosphorylation and altered substrate speci®city (Carrera et al, 1995).…”

Transitional Type 1 and 2 B Lymphocyte Subsets Are Differentially Responsive to Antigen Receptor Signaling

“…A naturally occurring point mutation (R28C) or genetargeted deletion of btk results in the B cell deficiency disorder termed x-linked immunodeficiency (xid) in mice (33)(34)(35)(36). Affected animals display a 50% reduction in the number of M splenic B cells (37)(38)(39). The M B cell deficiency in these mice is probably due to a failure of T2 B cell transition into M B cells.…”

Correction of the X-linked immunodeficiency phenotype by transgenic expression of human Bruton tyrosine kinase under the control of the class II major histocompatibility complex Ea locus control region

“…Mutations in the Btk gene (4) lead to X-linked agammaglobulinemia (XLA) in humans, which is characterized by an almost complete failure of pre-B cells to differentiate into mature B cells (5)(6)(7)(8). In the mouse, Btk defects result in a mild B cell disorder, X-linked immunodeficiency (xid), both in CBA͞N mice carrying an Arg-28 pleckstrin homology domain mutation, and in mice with targeted disruptions of Btk in their germ line (9)(10)(11)(12)(13).…”