Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The X-ray crystal structure of the pleckstrin homology (PH) domain from human dynamin has been refined to 2.2 A resolution. A seven-stranded beta sandwich of two orthogonal antiparallel beta sheets is closed at one corner by a C-terminal alpha helix. Opposite this helix are the three loops that vary most among PH domains. The basic fold is very similar to that of two other PH domains recently determined by nuclear magnetic resonance, confirming that PH domain with known structure is electrostatically polarized, with the three variable loops forming a positively charged surface. This surface includes the position of the X-linked immunodeficiency mutation in the Btk PH domain and may serve as a ligand-binding surface.
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PMID:Crystal structure at 2.2 A resolution of the pleckstrin homology domain from human dynamin. 795 89

Gap1(IP4BP), one of a member of Ras GTPase-activating proteins, has been identified as a specific inositol 1,3,4,5-tetrakisphosphate (IP4)-binding protein (Cullen, P. J., Hsuan, J. J., Truong, O., Letcher, A. J., Jackson, T. R., Dawson, A. P., and Irvine, R. F. (1995) Nature 386, 527-530). In this paper we describe Gap1(m), which is closely related to Gap1(IP4BP), to also be an IP4-binding protein and show that the pleckstrin homology domain (PH) is the central IP4-binding domain by expressing fragments of the mouse Gap1(m) in Escherichia coli as fusion proteins and examining their activities. However, in addition to the PH domain, an adjacent GAP-related domain and carboxyl terminus are required for high affinity specific IP4 binding. The PH domain is highly conserved in the Gap1 family and also has striking homology to the amino-terminal region of Bruton's tyrosine kinase. Substitution of Cys for Arg at position 628 in the PH domain corresponding to the mutation of Bruton's tyrosine kinase observed in X-linked immunodeficiency mice results in a dramatic reduction of IP4 binding activity as well as phospholipid binding capacity of Gap1(m). This mutant also showed the GAP activity against Ha-Ras to be similar to that of the wild type Gap1(m). Our results suggest that the PH domain of Gap1(m) functions as a modulatory domain of GAP activity by binding IP4 and phospholipids.
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PMID:Structure-function relationships of the mouse Gap1m. Determination of the inositol 1,3,4,5-tetrakisphosphate-binding domain. 870 43

Bruton's tyrosine kinase (Btk), a cytoplasmic protein-tyrosine kinase, plays a pivotal role in B cell activation and development. Mutations in the pleckstrin homology (PH) domain of the Btk gene cause human X-linked agammaglobulinemia (XLA) and murine X-linked immunodeficiency (Xid). In this paper, we report that the PH domain of Btk functions as an inositol 1,3,4,5-tetrakisphosphate (IP4), inositol 1,3,4,5,6-pentakisphosphate, and inositol 1,2,3,4,5,6-hexakisphosphate (IP6) binding domain (Kd of approximately 40 nM for IP4), and that all of the XLA (Phe replaced by Ser at position 25 (F25S), R28H, T33P, V64F, and V113D) and Xid mutations (R28C) found in the PH domain result in a dramatic reduction of IP4 binding activity. Furthermore, the rare alternative splicing variant, with 33 amino acids deleted in the PH domain, corresponding to exon 3 of the Btk gene, also impaired IP4 binding capacity. In contrast, a gain-of-function mutant called Btk*, which carries a E41K mutation in the PH domain, binds IP6 with two times higher affinity than the wild type. Our data suggest that B cell differentiation is closely correlated with the IP4 binding capacity of the PH domain of Btk.
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PMID:Mutation of the pleckstrin homology domain of Bruton's tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-tetrakisphosphate binding capacity. 893 85

Pleckstrin is a 40 kDa substrate for protein kinase C found in platelets and neutrophils. Based upon its sequence, pleckstrin contains two of the recently-described PH domains that are thought to be binding motifs for phosphatidyl 4,5-bisphosphate (PIP2) and/or G protein beta gamma heterodimers (G beta gamma). In the present studies we have examined the interaction between pleckstrin and G beta gamma by incubating pleckstrin fusion proteins with lysates from human platelets. In this analysis, both the N-terminal and C-terminal PH domains from pleckstrin bound G beta gamma in vitro, as did peptides containing as little as the first 30 residues of the C-terminal pleckstrin PH domain. Introduction of a point mutation into this region, analogous to the mutation in the Btk PH domain that causes X-linked immunodeficiency disease (XID) in mice, dramatically disrupted this interaction. We propose that pleckstrin may interact with G beta gamma, and that one potential site for this interaction involves the first 30 residues of pleckstrin's C-terminal PH domain.
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PMID:A site of interaction between pleckstrin's PH domains and G beta gamma. 898 77

X-linked agammaglobulinaemia (XLA) is an immunodeficiency caused by mutations in Bruton's tyrosine kinase (Btk) and is characterized by an almost complete arrest of B cell development. We analysed expression of Btk in B lymphoblastoid cell lines (BLCL) derived from four unrelated XLA patients. In one patient, with a 3 x 5 kb genomic deletion encompassing the first (untranslated) exon, mRNA levels and in vitro kinase activities were very low. The patient manifested a mild phenotype with a delayed onset of the disease. Another mutation, in which the intron 3 donor splice site is lost, was also associated with very low mRNA levels and an absence of detectable Btk protein. Patients with this mutation showed extensive heterogeneity of the immunological phenotype. In the BLCL of a third patient, with an Arg288 substitution in the SH2 domain, the mutation did not appear to affect the expression level, nor to abrogate in vitro phosphorylation activity. In the BLCL of the fourth patient, with an Arg28 mutation in the PH domain, tyrosine kinase activity in BTK precipitates appeared to be decreased compared with control BLCL.
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PMID:Expression of Bruton's tyrosine kinase in B lymphoblastoid cell lines from X-linked agammaglobulinaemia patients. 903 Aug 58

Mutations of the Bruton's tyrosine kinase (Btk) gene cause X linked agammaglobulinaemia (XLA). This inherited immunodeficiency disease causes an arrest in B cell differentiation of pre-B cells to mature B cells. In this study we report the characterisation of mutations in the Btk gene in 10 unrelated XLA families. The screening approach we used was based on reverse transcriptase PCR and direct cycle sequencing of the amplified products followed by analysis of the observed mutations at the level of genomic DNA. The single strand confirmation polymorphism (SSCP) technique was used for assessment of the carriers in some of these families. Various mutations throughout the coding gene were observed, including missense and nonsense mutations, a deletion, and several splicing defects. None of the mutations except one has been previously described. There were three point mutations resulting in a single amino acid substitution. One of these missense mutations was observed in a conserved region of the PH domain, the other two were found in the src homology domain 2 that is involved in phosphotyrosyl peptide binding. Two mutations were single base pair substitutions resulting in premature stop codons. In four patients abnormal Btk transcripts were found that were the result of aberrant splicing. One small deletion was observed causing a frameshift and a secondary premature termination signal. Characterisation of the mutations responsible for XLA allowed us to diagnose the disease conclusively and identify the phenotypically normal female carriers.
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PMID:Identification of novel Bruton's tyrosine kinase mutations in 10 unrelated subjects with X linked agammaglobulinaemia. 919 69

We previously reported that the pleckstrin homology (PH) domain of Bruton's tyrosine kinase (Btk) binds Ins(1,3,4,5)P4 and that missense mutations in this domain which cause either human X-linked agammaglobulinemia (XLA) or murine X-linked immunodeficiency (Xid) also dramatically reduce the Ins(1,3,4,5)P4 binding activity. In this paper, we describe the inositol phosphate binding specificity of the Btk PH domain and different inositol polyphosphate binding properties among the PH domains of Tec family kinases. Our results suggest that certain inositol phosphates and/or phosphoinositides are physiological ligands of some Tec family kinases and that Tec family members are differently regulated by inositol molecules.
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PMID:Characterization of the pleckstrin homology domain of Btk as an inositol polyphosphate and phosphoinositide binding domain. 924 Apr 35

Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunodeficiencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Genetic and biochemical evidence implicates Btk as a key component of several B cell signaling pathways. Activation of Btk by a point mutation (E41K) within the PH domain (Btk*) results in fibroblast transformation and is correlated with increased membrane localization of Btk. When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction. To determine whether membrane association is sufficient to activate Btk, we targeted Btk to the plasma membrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive membrane association greatly enhanced the ability of Btk to transform Rat2 fibroblasts in the presence of high levels of Src activity. All membrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required membrane localization, Btk kinase activity, transphosphorylation by Src family kinases, and an intact SH2 domain but not the PH or SH3 domains. These data suggest that membrane localization is a critical early step in Btk activation.
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PMID:Constitutive membrane association potentiates activation of Bruton tyrosine kinase. 933 13

Bruton's tyrosine kinase (Btk) is required for normal B-cell development, as defects in Btk lead to X-linked immunodeficiency (xid) in mice and X-linked agammaglobulinemia (XLA) in humans. Here we demonstrate a functional interaction between the multifunctional transcription factor TFII-I and Btk. Ectopic expression of wild-type Btk enhances TFII-I-mediated transcriptional activation and its tyrosine phosphorylation in transient-transfection assays. Mutation of Btk in either the PH domain (R28C, as in the murine xid mutation) or the kinase domain (K430E) compromises its ability to enhance both the tyrosine phosphorylation and the transcriptional activity of TFII-I. TFII-I associates constitutively in vivo with wild-type Btk and kinase-inactive Btk but not xid Btk. However, membrane immunoglobulin M cross-linking in B cells leads to dissociation of TFII-I from Btk. We further show that while TFII-I is found in both the nucleus and cytoplasm of wild-type and xid primary resting B cells, nuclear TFII-I is greater in xid B cells. Most strikingly, receptor cross-linking of wild-type (but not xid) B cells results in increased nuclear import of TFII-I. Taken together, these data suggest that although the PH domain of Btk is primarily responsible for its physical interaction with TFII-I, an intact kinase domain of Btk is required to enhance transcriptional activity of TFII-I in the nucleus. Thus, mutations impairing the physical and/or functional association between TFII-I and Btk may result in diminished TFII-I-dependent transcription and contribute to defective B-cell development and/or function.
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PMID:Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton's tyrosine kinase. 1037 51


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