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: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The Tec family is a recently emerging subfamily among nonreceptor type protein-tyrosine kinases (PTKs) consisting of Tec, Txk, Btk, Bmx, and Itk/Tsk/Emt. They have a long amino-terminal unique region containing a pleckstrin homology domain and a Tec-homology domain. We could previously show that, through the Tec-homology domain, Tec is bound to Lyn kinase both in vitro and in vivo. Because Tec is coexpressed with Lyn in many hematopoietic cell types, it has been intriguing to investigate the biological role of the Tec-Lyn association. Here we demonstrate that Lyn can phosphorylate tyrosine residues of the Tec protein, and thereby activate Tec in 3T3 fibroblasts. However, coexpression of Tec has little effect on the phospho-tyrosine-contents of Lyn. By using the in vitro kinase assay and the yeast system, we could prove that the Tec protein is a direct substrate of the Lyn kinase both in vitro and in vivo. From this evidence we conclude that Tec acts downstream of Lyn in intracellular signaling pathways. This is a novel case where one PTK is phosphorylated and regulated by another.
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PMID:Tec protein-tyrosine kinase is an effector molecule of Lyn protein-tyrosine kinase. 862 Oct 63

Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development. Overexpression of Btk with a Src family kinase increases tyrosine phosphorylation and catalytic activity of Btk. This occurs by transphosphorylation at Y551 in the Btk catalytic domain and the enhancement of Btk autophosphorylation at a second site. A gain-of-function mutant called Btk* containing E41 to K change within the pleckstrin homology domain induces fibroblast transformation. Btk* enhances the transphosphorylation of Y551 by endogenous Src family tyrosine kinases and autophosphorylation at the second site. We mapped the major Btk autophosphorylation site to Y223 within the SH3 domain. Mutation of Y223 to F blocks Btk autophosphorylation and dramatically potentiates the transforming activity of Btk* in fibroblasts. The location of Y223 in a potential ligand-binding pocket suggests that autophosphorylation regulates SH3-mediated signaling by Btk.
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PMID:Regulation of Btk function by a major autophosphorylation site within the SH3 domain. 863 Jul 36

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

A point mutation in the pleckstrin homology domain of the mouse Bruton's tyrosine kinase (btk) gene results in an X-linked immune defect, Xid, characterized by immunologic unresponsiveness to polymeric carbohydrate Ags. In Xid mice, B cells specific for phosphocholine (PC) do not develop in peripheral lymphoid tissues because they either fail to be positively selected from the marrow or they are clonally deleted via an Ag-driven, receptor-mediated process. Overexpression of the bcl-2 gene allows PC-specific B cells to survive and mature in Xid mukappa anti-PC transgenic mice, but PC-specific B cells are not rescued by bcl-2 in Xid mu-only transgenic mice. The failure of bcl-2 to rescue PC-specific B cells, in mu-only transgenic mice suggests that either it does not correct the btk defect in the Ag-driven selection process that occurs in pre-B cells and/or in very immature B cells or that a btk-dependent proliferative phase is required for the selection and amplification of the PC-specific B cells in mu-only transgenic mice. The rescue of PC-specific B cells in mukappa transgenic mice indicates that bcl-2 can alter receptor-mediated B cell selection at late stages in B cell development. The rescued PC-specific B cells in Xid male mice do not exhibit an altered proliferation profile in response to B cell-stimulating agents compared with B cells from unmanipulated Xid mice; thus, they fail to respond to soluble anti-mu, or PC-dextran, but they proliferate in response to PC, anti-mu, or anti-id conjugated to Sepharose.
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PMID:bcl-2 alters the antigen-driven selection of B cells in mukappa but not in mu-only Xid transgenic mice. 875 9

X-linked agammaglobulinemia is a heritable immunodeficiency disease caused by a differentiation abnormality, resulting in the virtual absence of B lymphocytes and plasma cells. The affected gene encodes a cytoplasmic protein tyrosine kinase, Bruton's agammaglobulinemia tyrosine kinase, designated Btk. Btk and the other family members, Tec, ltk and Bmx, contain five regions, four of which are common structural and functional modules that are found in other signaling proteins. Mutations affect all domains of the gene, but amino acid substitutions seem to be confined to certain regions. More than 150 unique mutations have been identified and are collected in a mutation database, BTKbase. Here we discuss the three-dimensional structural implications of such mutations and their putative functional role. Of special interest are mutations affecting the pleckstrin homology domain, as Btk is the only disease-associated protein so far reported to carry mutations in this particular module.
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PMID:X-linked agammaglobulinemia (XLA): a genetic tyrosine kinase (Btk) disease. 888 20

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

Phosphatidylinositol (PI) 3-kinase is a cytoplasmic signaling molecule that is recruited to activated growth factor receptors after growth factor stimulation of cells. Activation of PI 3-kinase results in increased intracellular levels of 3' phosphorylated inositol phospholipids and the induction of signaling responses, including the activation of the protein kinase Akt, which is also known as RAC-PK or PKB. We tested the possibility that the phospholipid products of PI 3-kinase directly mediate the activation of Akt. We have previously described a constitutively active PI 3-kinase, p110, which can stimulate Akt activity. We used purified p110 protein to generate a series of 3' phosphorylated inositol phospholipids and tested whether any of these lipids could activate Akt in vitro. Phospholipid vesicles containing PI3,4 bisphosphate (P2) specifically activated Akt in vitro. By contrast, the presence of phospholipid vesicles containing PI3P or PI3,4,5P3 failed to increase the kinase activity of Akt. Akt could also be activated by synthetic dipalmitoylated PI3,4P2 or after enzymatic conversion of PI3,4,5P3 into PI3,4P2 with the signaling inositol polyphosphate 5' phosphatase SIP. We show that PI3,4P2-mediated activation is dependent on a functional pleckstrin homology domain in Akt, since a point mutation in the pleckstrin homology domain abrogated the response to PI3,4P2. Our findings show that a phospholipid product of PI 3-kinase can directly stimulate an enzyme known to be an important mediator of PI 3-kinase signaling.
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PMID:A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. 897 14

Bruton's tyrosine kinase (Btk) is essential for B cell activation, but downstream targets of Btk have not been defined. We now describe a protein, BAP-135, that is associated with Btk in B cells and is a substrate for phosphorylation by Btk. BAP-135, which exhibits no detectable homology to known proteins, contains six occurrences of a hitherto undescribed amino acid repeat and two motifs, similar to the Src autophosphorylation site, that represent potential targets for tyrosine phosphorylation. The pleckstrin homology domain of Btk comprises the principal site of BAP-135 binding. Btk-dependent phosphorylation of BAP-135 is abolished by mutations that impair activation of Btk by Src-related kinases. Btk and BAP-135 exist in a complex before B cell antigen receptor (BCR) engagement; in response to BCR crosslinking, BAP-135 is transiently phosphorylated on tyrosine. Taken together, these observations suggest that BAP-135 may reside downstream of Btk in a signaling pathway originating at the BCR.
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PMID:BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement. 901 31


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