Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked agammaglobulinemia (XLA) is an inherited human immunodeficiency disease, characterized by an arrest in B-cell development, which results in a dramatic decrease in immunoglobulin production. The gene product defective in XLA has been identified as a cytoplasmic protein tyrosine kinase, named Bruton's tyrosine kinase (Btk). The dramatic XLA phenotype indicates a critical role for Btk in the regulation of B-cell development. However, neither external stimuli leading to Btk activation nor any of its in vivo substrates have thus far been identified, and the mechanism of disease induction remains unexplained. We report here that stimulation of the B-cell antigen receptor (membrane immunoglobulin) on mature B-cells induces tyrosine phosphorylation of Btk in vivo, accompanied by an increase in its kinase activity in vitro. These results place Btk in the B-cell receptor signal transduction pathway, which is known to be essential in driving B-cell differentiation.
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PMID:B-cell antigen receptor stimulation activates the human Bruton's tyrosine kinase, which is deficient in X-linked agammaglobulinemia. 792 28

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

We have produced physical maps of the proximal part of Xq22, containing the Bruton's tyrosine kinase (BTK) and alpha-galactosidase A (GLA) gene loci, using long range physical mapping techniques and yeast artificial chromosomes (YACs). These maps reveal five previously unidentified CpG islands which could indicate the presence of other genes in this region.
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PMID:Physical mapping in the region of the Bruton's tyrosine kinase and alpha-galactosidase A gene loci in proximal Xq22. 798 38

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disease associated with a block in differentiation from pre-B to B cells. The XLA gene encodes a 659 amino acids cytoplasmic protein tyrosine kinase named btk (Bruton's tyrosine kinase). The few btk gene alterations so far reported in XLA patients are heterogenous and distributed in all domains of the btk protein. They appear to be responsible for a range of B cell immunodeficiency disorders of variable severity. Rare families in which XLA is inherited together with isolated growth hormone deficiency (IGHD) have been reported. Genetic analysis has shown that this disease association maps to the same region of the X chromosome as XLA, but whether the two phenotypes are caused by a common or different developmental or biochemical mechanism is unknown. We have analyzed the btk gene of a patient with XLA and IGHD. RT-PCR analysis of btk transcripts, sequencing data obtained from cDNA and genomic DNA and in vitro splicing assays showed that an intronic point mutation (1882 + 5G-->A) is responsible for skipping of an exon located in the tyrosine kinase domain. This exon-skipping event results in a frameshift leading to a premature stop codon 14 amino acids downstream, and in the loss of the last 61 residues of the carboxy-terminal end of the protein. Although we studied a sporadic case, the results suggest that an alteration of the btk gene might cause this unusual phenotype.
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PMID:An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. 801 27

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

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disease in man, reflecting an arrest in differentiation of pre-B cells to mature B cell stages. The gene defective in XLA has been identified as a cytoplasmic protein tyrosine kinase, named btk (Bruton's tyrosine kinase). Here we report the characterization of mutations in the btk gene of five unrelated XLA families. Amplified products were generated from cDNA, cloned and sequenced. Three single point mutations and two small insertions were identified. One of the point mutations and the two insertions created stop codons that would lead to truncated btk proteins. In one XLA patient we found a single basepair substitution that altered the highly conserved Arg288 within the SH2 domain and would therefore abrogate interactions with substrate phosphotyrosines. In another XLA patient a single basepair substitution was observed that altered the conserved Arg28 residue in the N-terminal unique region of unknown function. This residue is also mutated in the xid mouse, which has a different, less severe, B cell deficiency. We conclude that a similar mutation in the btk gene leads in man to an almost complete arrest at an early stage of B cell differentiation, but in the mouse to only limited B cell abnormalities.
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PMID:Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice. 816 18

X-linked agammaglobulinemia (XLA) is an immunodeficiency disease in man, resulting from an arrest in early B cell differentiation. The gene defective in XLA has recently been identified and encodes a cytoplasmic protein tyrosine kinase, named Bruton's tyrosine kinase (btk), essential for cell differentiation and proliferation at the transition from pre-B to later B cell stages. In this study we investigated btk expression by Northern blotting experiments in a series of human (precursor-) B cell lines, acute lymphoblastic leukemias and plasmacytomas. btk was found to be already expressed in very early stages of B cell differentiation, even prior to immunoglobulin (Ig) heavy (H) or light (L) chain gene rearrangements. Transcripts were also detected at the pre-B cell stage and in mature B cells, irrespective of the Ig H chain class expressed. Approximately at the transition from mature B cells to plasma cells, expression of the btk gene is down-regulated. In addition, the btk gene was found to be expressed in myeloid cell lines and acute myeloid leukemias. btk expression in myeloid cells is probably not a prerequisite for myeloid differentiation, since myeloid cells in XLA patients seem not to be affected. No btk expression was found in T-lineage cells. The btk expression profile, i.e. from early precursor-B cell stages preceding Ig rearrangement up to mature B cells, supports the hypothesis that the XLA defect resides in a critical step of B cell development which is independent of the Ig gene recombination machinery.
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PMID:The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. 825 24

The cytoplasmic tyrosine kinase, Bruton's tyrosine kinase (Btk, formerly bpk or atk), is crucial for B cell development. Loss of kinase activity results in the human immunodeficiency, X-linked agammaglobulinemia, characterized by a failure to produce B cells. In the murine X-linked immunodeficiency (XID), B cells are present but respond abnormally to activating signals. The Btk gene, btk, was mapped to the xid region of the mouse X chromosome by interspecific backcross analysis. A single conserved residue within the amino terminal unique region of Btk was mutated in XID mice. This change in xid probably interferes with normal B cell signaling mediated by Btk protein interactions.
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PMID:Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. 833 1

The genetic defect associated with two closely related primary immunodeficiencies was recently identified as a deficiency of function of a new cytoplasmic tyrosine kinase, Bruton's tyrosine kinase (Btk). Btk and related genes expressed primarily in hematopoietic cells (Itk, Tec, Drsrc28C and Txk) comprise a new subfamily of cytoplasmic tyrosine kinases. These proteins share significant structural and sequence homology including an amino-terminal pleckstrin homology (PH) domain not present in other cytoplasmic tyrosine kinase subfamilies. This domain plays an essential role in regulation and function of the Btk subfamily proteins. Genetic evidence supports a critical role for Btk in B-lineage development. Additional studies demonstrate activation of these proteins in multiple hematopoietic signaling pathways including the B cell antigen receptor, several cytokine receptors, and a potential novel role in heterotrimeric G protein associated receptor signaling.
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PMID:The Btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function. 852 28

The X-ray crystal structure of the high affinity complex between the pleckstrin homology (PH) domain from rat phospholipase C-delta 1 (PLC-delta 1) and inositol-(1,4,5)-trisphosphate (Ins(1,4,5)P3) has been refined to 1.9 A resolution. The domain fold is similar to others of known structure. Ins(1,4,5)P3 binds on the positively charged face of the electrostatically polarized domain, interacting predominantly with the beta 1/beta 2 and beta 3/beta 4 loops. The 4- and 5-phosphate groups of Ins(1,4,5)P3 interact much more extensively than the 1-phosphate. Two amino acids in the PLC-delta 1 PH domain that contact Ins(1,4,5)P3 have counterparts in the Bruton's tyrosine kinase (Btk) PH domain, where mutational changes cause inherited agammaglobulinemia, suggesting a mechanism for loss of function in Btk mutants. Using electrostatics and varying levels of head-group specificity, PH domains may localize and orient signaling proteins, providing a general membrane targeting and regulatory function.
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PMID:Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain. 852 4


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