Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The surface membrane molecule CD5 is expressed on mature T cells and on the B-1a subpopulation of B cells. These CD5 positive B cells express an antibody repertoire with a relatively high frequency of self-reactivity. There is uncertainty about the origins of CD5 B cells and the reasons for this are reviewed. Recent reports which relate to the lineage/selection debate are discussed. For instance, an increase in the frequency of CD5 B cells is a feature of several genetically determined polysystem autoimmune syndromes. In the case of motheaten (me, mev) the pathogenesis of this increase in CD5 B cells is not yet understood, even though the mutation has been mapped to the Hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Another mutation which affects B cell development, X-linked immunodeficiency (xid), encodes a point mutation in a B cell cytoplasmic tyrosine kinase. Expression of xid in otherwise normal mice causes a lack of CD5 B cells and a shift in the antibody repertoire. Interestingly, expression of both xid and motheaten results in an amelioration of autoantibody production. Evidence is presented that in B cells regulation of expression of CD5 can occur at the level of mRNA and that cross-linking of sIgM can induce the accumulation of CD5 mRNA. The overall concept advanced is that cells expressing natural autoantibodies are triggered via sIgM ligation to become CD5 B cells.
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PMID:Activation of B-cells by sIgM cross-linking induces accumulation of CD5 mRNA. 753 70

Bruton's tyrosine kinase (BTK) is a nonreceptor tyrosine kinase critical for B cell development and function. Mutations in BTK result in X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Using a random mutagenesis scheme, we isolated a gain-of-function mutant called BTK* whose expression drives growth of NIH 3T3 cells in soft agar. BTK* results from a single point mutation in the pleckstrin homology (PH) domain, where a Glu is replaced by Lys at residue 41. BTK* shows an increase in phosphorylation on tyrosine residues and an increase in membrane targeting. Transforming activity requires kinase activity, a putative autophosphorylation site, and a functional PH domain. Mutation of the SH2 or SH3 domains did not affect the activity of BTK*. Expression of BTK* could also relieve IL-5 dependence of a B lineage cell line. These results show that transformation activation and regulation of BTK are critically dependent on the PH domain.
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PMID:Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain. 753 39

CD38 is a 42 kDa membrane-associated ectoenzyme expressed by a large proportion of human and mouse lymphocytes. Agonistic antibodies to CD38 induce a strong proliferative response in lymphocytes additionally co-stimulated with other growth co-factors such as IL-4, IL-2 plus accessory cells or sub-mitogenic doses of endotoxin. We show here that B lymphocytes from unstimulated X-linked immunodeficient (xid) mice are unresponsive to CD38 stimulation, both in terms of proliferative response and surface antigen modulation. This CD38 unresponsiveness is evident in the presence of excess quantities of, and normal responses to, the accessory growth co-stimulants required for this response. CD38 molecules expressed on xid B cells are normal in terms of expression levels, size and enzymatic activity, suggesting that CD38 unresponsiveness reflects a down-stream signaling defect. In light of the recent proposal that the xid gene encodes a tyrosine kinase called Bruton's tyrosine kinase (btk), these data suggest that btk is either an integral component or an indirect regulator of the CD38-induced signal transduction pathway.
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PMID:CD38 unresponsiveness of xid B cells implicates Bruton's tyrosine kinase (btk) as a regular of CD38 induced signal transduction. 773 14

Gene defects causing three X-linked human immunodeficiencies, agammaglobulinemia (XLA), hyper-IgM syndrome (HIGM), and X-linked severe combined immunodeficiency (SCID), have been identified. These represent the first human disease phenotypes associated with three gene families already recognized to be important in lymphocyte development and signaling: XLA is caused by mutations of a B-cell specific intracellular tyrosine kinase; HIGM by mutations in the tumor necrosis factor-related CD40 ligand, through which T cells deliver helper signals by direct contact with B-cell CD40; and SCID by mutations in the gamma chain of the lymphocyte receptor for interleukin-2. The great variety of patient mutations in all three genes represent both a challenge for genetic diagnosis and a resource for dissecting molecular domains and physiologic functions of the gene products.
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PMID:Molecular basis for three X-linked immune disorders. 784 38

The molecular basis for three well-defined X-linked diseases has recently been identified. In X-linked agammaglobulinemia, the gene encoding a novel cytoplasmic tyrosine kinase (btk) expressed by B cells is defective. This B-cell-specific kinase belongs to a new subfamily of tyrosine kinases. The molecular defect in X-linked hyper IgM affects the gene encoding the CD40 ligand (CD40L, gp39) on T cells. This protein binds to its natural receptor, CD40, expressed constitutively by B cells. The ligand-receptor interaction initiates B-cell proliferation and isotype switching. The molecular defect in X-linked severe combined immunodeficiency disease has been assigned to the gene encoding the gamma chain of the interleukin-2 receptor (IL-2R gamma), which is constitutively expressed by T cells and is involved in the formation of high and intermediate affinity IL-2R complexes. IL-2R-gamma is responsible for the failure of X-linked severe combined immunodeficiency disease T and B lymphocytes to respond to IL-2-dependent signals.
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PMID:Advances in X-linked immunodeficiency diseases. 790 59

In the past year, researchers have identified the genes responsible for X-linked severe combined immunodeficiency (encoding a cytokine receptor protein), X-linked agammaglobulinemia (encoding a cytoplasmic tyrosine kinase) and X-linked hyper IgM syndrome (encoding the ligand for CD40). Although these three genes are completely unrelated, it is of interest that all are lineage-specific genes that are involved in the control of lymphocyte proliferation or differentiation.
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PMID:X-linked immunodeficiencies. 791 18

The genetic defect associated with human X-linked agammaglobulinemia and murine X-linked immunodeficiency was recently shown to result from lack of function of a new cytoplasmic tyrosine kinase, called Bruton's tyrosine kinase (Btk). The phenotypes associated with these immunodeficiencies indicate that Btk plays a critical role in B-lymphocyte development. The distinctive protein structure of Btk and preliminary functional studies suggest that Btk may act in a novel manner in a variety of signaling pathways.
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PMID:Role of Bruton's tyrosine kinase in immunodeficiency. 794 52

A gene for a novel, putative cytoplasmic tyrosine kinase, TXK has been isolated from a human peripheral blood cDNA library. The complete nucleotide sequence of the cDNA indicates that it is related most closely to EMT, a tyrosine kinase of T cells and to the B-cell tyrosine kinase Btk, which is mutated in X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency disease (XID) in mouse. TXK, like BTK, is a member of the Tec sub-family of Src-type (non-receptor) tyrosine kinases. Like similar Tec sub-family members, and unlike the other Src kinases, TXK lacks both the N-terminal myristylation signal and the C-terminal regulatory tyrosine. TXK expression is detected primarily in T cells and some myeloid cell lines but not in a number of other cell types. TXK shares 60% amino acid homology with EMT and 57% with BTK over the SH3, SH2 (Src-homology) and catalytic domains but unlike BTK, EMT and tec, it lacks Gap 1 homology and steroid hormone receptor homology in the N-terminal region. Genomic clones containing TXK have been isolated and hybridize to chromosome position 4p12.
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PMID:TXK, a novel human tyrosine kinase expressed in T cells shares sequence identity with Tec family kinases and maps to 4p12. 795 Dec 33

Bruton's tyrosine kinase (Btk) is a recently described B-cell-specific tyrosine kinase. Mutations in this gene lead to human X chromosome-linked agammaglobulinemia and murine X-linked immunodeficiency. Although genetic evidence strongly suggests that Btk plays a crucial role in B-lymphocyte differentiation and activation, its precise mechanism of action remains unknown, primarily because the proteins that it interacts with have not yet been identified. Here, we show that Btk interacts with Src homology 3 domains of Fyn, Lyn, and Hck, protein-tyrosine kinases that get activated upon stimulation of B- and T-cell receptors. These interactions are mediated by two 10-aa motifs in Btk. An analogous site with the same specificity is also present in Itk, the T-cell-specific homologue of Btk. Our data extend the range of interactions mediated by Src homology 3 domains and provide an indication of a link between Btk and established signaling pathways in B lymphocytes.
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PMID:Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction. 805 72

Within a short time interval the specific gene defects causing three X-linked human immunodeficiencies, agammaglobulinemia (XLA), hyper-IgM syndrome (HIGM), and severe combined immunodeficiency (XSCID), have been identified. These represent the first human disease phenotypes associated with each of three gene families already recognized to be important in lymphocyte development and signaling: XLA is caused by mutations of a B cell-specific intracellular tyrosine kinase; HIGM, by mutations in the TNF-related CD40 ligand, through which T cells deliver helper signals by direct contact with B cell CD40; and XSCID, by mutations in the gamma chain of the lymphocyte receptor for IL-2. Each patient mutation analyzed to date has been unique, representing both a challenge for genetic diagnosis and management and an important resource for dissecting molecular domains and understanding the physiologic function of the gene products.
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PMID:Molecular and genetic basis of X-linked immunodeficiency disorders. 819 17


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