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

Exposure of B-lineage lymphoid cells to ionizing radiation induces an elevation of c-jun proto-oncogene mRNA levels. This signal is abrogated by protein-tyrosine kinase (PTK) inhibitors, indicating that activation of an as yet unidentified PTK is mandatory for radiation-induced c-jun expression. Here, we provide experimental evidence that the cytoplasmic tyrosine kinases BTK, SYK, and LYN are not required for this signal. Lymphoma B-cells rendered deficient for LYN, SYK, or both by targeted gene disruption showed increased c-jun expression levels after radiation exposure, but the magnitude of the stimulation was lower than in wild-type cells. Thus, these PTKs may participate in the generation of an optimal signal. Notably, an inhibitor of JAK-3 (Janus family kinase-3) abrogated radiation-induced c-jun activation, prompting the hypothesis that a chicken homologue of JAK-3 may play a key role in initiation of the radiation-induced c-jun signal in B-lineage lymphoid cells.
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PMID:Role of tyrosine kinases in induction of the c-jun proto-oncogene in irradiated B-lineage lymphoid cells. 965 74

Phosphatidylinositol 3-kinase (PI3K) mediates a variety of cellular responses by generating PtdIns(3,4)P2 and PtdIns(3,4,5)P3. These 3-phosphoinositides then function directly as second messengers to activate downstream signaling molecules by binding pleckstrin homology (PH) domains in these signaling molecules. We have established a novel assay in the yeast Saccharomyces cerevisiae to identify proteins that bind PtdIns(3,4)P2 and PtdIns(3,4,5)P3 in vivo which we have called TOPIS (Targets of PI3K Identification System). The assay uses a plasma membrane-targeted Ras to complement a temperature-sensitive CDC25 Ras exchange factor in yeast. Coexpression of PI3K and a fusion protein of activated Ras joined to a PH domain known to bind PtdIns(3,4)P2 (AKT) or PtdIns(3,4,5)P3 (BTK) rescues yeast growth at the non-permissive temperature of 37 degreesC. Using this assay, we have identified several amino acids in the beta1-beta2 region of PH domains that are critical for high affinity binding to PtdIns(3,4)P2 and/or PtdIns(3,4,5)P3, and we have proposed a structural model for how these PH domains might bind PI3K products with high affinity. From these data, we derived a consensus sequence which predicts high-affinity binding to PtdIns(3, 4)P2 and/or PtdIns(3,4,5)P3, and we have identified several new PH domain-containing proteins that bind PI3K products, including Gab1, Dos, myosinX, and Sbf1. Use of this assay to screen for novel cDNAs which rescue yeast at the non-permissive temperature should provide a powerful approach for uncovering additional targets of PI3K.
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PMID:Identification and analysis of PH domain-containing targets of phosphatidylinositol 3-kinase using a novel in vivo assay in yeast. 973 15

Rlk/Txk is a member of the BTK/Tec family of tyrosine kinases and is primarily expressed in T lymphocytes. Unlike other members of this kinase family, Rlk lacks a pleckstrin homology (PH) domain near the amino terminus and instead contains a distinctive cysteine string motif. We demonstrate here that Rlk protein consists of two isoforms that arise by alternative initiation of translation from the same cDNA. The shorter, internally initiated protein species lacks the cysteine string motif and is located in the nucleus when expressed in the absence of the larger form. In contrast, the larger form is cytoplasmic. We show that the larger form is palmitoylated and that mutation of its cysteine string motif both abolishes palmitoylation and allows the protein to migrate to the nucleus. The cysteine string, therefore, is a critical determinant of both fatty acid modification and protein localization for the larger isoform of Rlk, suggesting that Rlk regulation is distinct from the other Btk family kinases. We further show that Rlk is phosphorylated and changes localization in response to T-cell-receptor (TCR) activation and, like the other Btk family kinases, can be phosphorylated and activated by Src family kinases. However, unlike the other Btk family members, Rlk is activated independently of the activity of phosphatidylinositol 3-kinase, consistent with its lack of a PH domain. Thus, Rlk has two distinct isoforms, each of which may have unique properties in signaling downstream from the TCR.
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PMID:rlk/TXK encodes two forms of a novel cysteine string tyrosine kinase activated by Src family kinases. 989 Oct 83

Bruton's tyrosine kinase, which is encoded by the BTK gene, is a cytoplasmic protein tyrosine kinase (PTK) crucial for B-cell development and differentiation. It belongs to the Tec family of PTKs containing several domains that are characteristic of signalling molecules. In humans, mutations that disrupt the function of this gene lead to the classical XLA syndrome (X-linked agammaglobulinaemia), a primary immunodeficiency mainly characterized by lack of mature B cells as well as low levels of immunoglobulins. In contrast, animal models of this disease such as the xid mice display profoundly milder XLA phenotype. BTK phosphorylation and activation in response to engagement of the B-cell receptor (BCR) by antigen is a dynamic process whereby a variety of proteins interact with each other and recruit signalling molecules resulting in a physiological response such as B-cell proliferation and antibody production. The main players, however, that participate in the intracellular downstream cascade have not yet been identified and are therefore under intense scrutiny in several laboratories. This review discusses certain aspects of BTK activation following receptor stimulation by agonists and how this event is translated into the biochemical signals within the cell that eventually lead to nuclear responses.
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PMID:Signalling of Bruton's tyrosine kinase, Btk. 1007 13

In a systematic effort to design potent inhibitors of the anti-apoptotic tyrosine kinase BTK (Bruton's tyrosine kinase) as anti-leukemic agents with apoptosis-promoting and chemosensitizing properties, we have constructed a three-dimensional homology model of the BTK kinase domain. Our modeling studies revealed a distinct rectangular binding pocket near the hinge region of the BTK kinase domain with Leu460, Tyr476, Arg525, and Asp539 residues occupying the corners of the rectangle. The dimensions of this rectangle are approximately 18 x 8 x 9 x 17 A, and the thickness of the pocket is approximately 7 A. Advanced docking procedures were employed for the rational design of leflunomide metabolite (LFM) analogs with a high likelihood to bind favorably to the catalytic site within the kinase domain of BTK. The lead compound LFM-A13, for which we calculated a Ki value of 1.4 microM, inhibited human BTK in vitro with an IC50 value of 17.2 +/- 0.8 microM. Similarly, LFM-A13 inhibited recombinant BTK expressed in a baculovirus expression vector system with an IC50 value of 2.5 microM. The energetically favorable position of LFM-A13 in the binding pocket is such that its aromatic ring is close to Tyr476, and its substituent group is sandwiched between residues Arg525 and Asp539. In addition, LFM-A13 is capable of favorable hydrogen bonding interactions with BTK via Asp539 and Arg525 residues. Besides its remarkable potency in BTK kinase assays, LFM-A13 was also discovered to be a highly specific inhibitor of BTK. Even at concentrations as high as 100 micrograms/ml (approximately 278 microM), this novel inhibitor did not affect the enzymatic activity of other protein tyrosine kinases, including JAK1, JAK3, HCK, epidermal growth factor receptor kinase, and insulin receptor kinase. In accordance with the anti-apoptotic function of BTK, treatment of BTK+ B-lineage leukemic cells with LFM-A13 enhanced their sensitivity to ceramide- or vincristine-induced apoptosis. To our knowledge, LFM-A13 is the first BTK-specific tyrosine kinase inhibitor and the first anti-leukemic agent targeting BTK.
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PMID:Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. 1009 45

A map has been assembled that extends from the XY homology region in Xq21.3 to proximal Xq24, approximately 20 Mb, formatted with 200 STSs that include 25 dinucleotide repeat polymorphic markers and more than 80 expressed sequences including 30 genes. New genes HTRP5, CAPN6, STPK, 14-3-3PKR, and CALM1 and previously known genes including BTK, DDP, GLA, PLP, COL4A5, COL4A6, PAK3, and DCX are localized; candidate loci for other disorders for which genes have not yet been identified, including DFN-2, POF, megalocornea, and syndromic and nonsyndromic mental retardation, are also mapped in the region. The telomeric end of the contig overlaps a yeast artificial chromosome (YAC) contig from Xq24-q26 and with other previously published contigs provides complete sequence-tagged site (STS)/YAC-based coverage of the long arm of the X chromosome. The order of published landmark loci in genetic and radiation hybrid maps is in general agreement. Combined with high-density STS landmarks, the multiple YAC clone coverage and integrated genetic, radiation hybrid, and transcript map provide resources to further disease gene searches and sequencing.
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PMID:Integrated STS/YAC physical, genetic, and transcript map of human Xq21.3 to q23/q24 (DXS1203-DXS1059). 1036 51

A novel homology model of the kinase domain of Janus kinase (JAK) 3 was used for the structure-based design of dimethoxyquinazoline compounds with potent and specific inhibitory activity against JAK3. The active site of JAK3 in this homology model measures roughly 8 A x 11 A x 20 A, with a volume of approximately 530 A3 available for inhibitor binding. Modeling studies indicated that 4-(phenyl)-amino-6,7-dimethoxyquinazoline (parent compound WHI-258) would likely fit into the catalytic site of JAK3 and that derivatives of this compound that contain an OH group at the 4' position of the phenyl ring would more strongly bind to JAK3 because of added interactions with Asp-967, a key residue in the catalytic site of JAK3. These predictions were consistent with docking studies indicating that compounds containing a 4'-OH group, WHI-P131 [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline], WHI-P154 [4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], and WHI-P97 [4-(3',5'-dibromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazolin e], were likely to bind favorably to JAK3, with estimated K(i)s ranging from 0.6 to 2.3 microM. These compounds inhibited JAK3 in immune complex kinase assays in a dose-dependent fashion. In contrast, compounds lacking the 4'-OH group, WHI-P79 [4-(3'-bromophenyl)-amino-6,7-dimethoxyquinazoline], WHI-P111 [4-(3'-bromo-4'-methylphenyl)-amino-6,7-dimethoxyquinazoline], WHI-P112 [4-(2',5'-dibromophenyl)-amino-6,7-dimethoxyquinazoline], WHI-P132 [4-(2'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], and WHI-P258 [4-(phenyl)-amino-6,7-dimethoxyquinazoline], were predicted to bind less strongly, with estimated K(i)s ranging from 28 to 72 microM. These compounds did not show any significant JAK3 inhibition in kinase assays. Furthermore, the lead dimethoxyquinazoline compound, WHI-P131, which showed potent JAK3-inhibitory activity (IC50 of 78 microM), did not inhibit JAK1 and JAK2, the ZAP/SYK family tyrosine kinase SYK, the TEC family tyrosine kinase BTK, the SRC family tyrosine kinase LYN, or the receptor family tyrosine kinase insulin receptor kinase, even at concentrations as high as 350 microM. WHI-P131 induced apoptosis in JAK3-expressing human leukemia cell lines NALM-6 and LC1;19 but not in melanoma (M24-MET) or squamous carcinoma (SQ20B) cells. Leukemia cells were not killed by dimethoxyquinazoline compounds that were inactive against JAK3. WHI-P131 inhibited the clonogenic growth of JAK3-positive leukemia cell lines DAUDI, RAMOS, LC1;19, NALM-6, MOLT-3, and HL-60 (but not JAK3-negative BT-20 breast cancer, M24-MET melanoma, or SQ20B squamous carcinoma cell lines) in a concentration-dependent fashion. Potent and specific inhibitors of JAK3 such as WHI-P131 may provide the basis for the design of new treatment strategies against acute lymphoblastic leukemia, the most common form of childhood cancer.
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PMID:Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. 1038 46

The title compound, C11H8Br2N2O2 (LFM-A13), is the first reported BTK-specific tyrosine kinase inhibitor and the first antileukemic agent targeting BTK (Bruton's tyrosine kinase). The crystal structure showed that the molecule adopts an approximately planar conformation aided by an intramolecular hydrogen bond formed between the hydroxyl group and the amide carbonyl group. The dihedral angle between the phenyl ring and the plane defined by the N-C-C=C-CH3 group is 8.2 (6) degrees. The crystal packing shows an additional weak intermolecular hydrogen bond between the hydroxyl group and the amide carbonyl-O atom of the centrosymmetrically related molecule.
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PMID:Alpha-cyano-N-(2,5-dibromophenyl)-beta-hydroxybut-2-enamide. 1048 6

Granzymes are a family of serine proteases exclusively detected in the granules of cytotoxic lymphocytes, and in mice at least eight granzymes, A to G and K, have been identified. Except for granzymes A and B, which activate the apoptotic pathway, little is known about the exact functions of the other granzymes. We have found that the granzyme D transcript is selectively expressed in functional hematopoietic stromal lines as well as primary stromal cells. Stromal lines supported growth of a pre-T lymphoma clone BTK at an efficiency proportional to the expression level of granzyme D, while a stromal line lacking granzyme D failed to do so. When the defective stromal line was transfected with granzyme D cDNA, it could efficiently support the growth of BTK cells. The results indicate that granzyme D expressed in the stromal cells plays an important role in stromal cell-lymphocyte interaction.
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PMID:Selective expression and function of granzyme D in lymphohematopoietic stromal cells. 1054 6

Mutations in the Bruton's tyrosine kinase (BTK ) gene are responsible for X-linked Agammaglobulinemia (XLA), an immunodeficiency caused by a block in B cell differentiation. Non Isotopic RNAse Cleavage Assay (NIRCA), followed by sequencing was used to screen for BTK mutations in 11 Italian XLA patients. Nine novel mutations were identified: 6 missense (Y39S, L512P, L512Q, R544G, S578Y, E589K), one non-sense (Q260X), one frameshift (1599-1602del GCGC) and one in-frame insertion (2037-2038insTTTTAG), that represents the first case of premature stop codon introduction in the BTK coding frame. These data support the high molecular heterogeneity of BTK gene in XLA disease and provide new insight to the diagnosis and to the role of BTK domain in XLA and in B cell signal transduction and development. Hum Mutat 15:117, 2000.
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PMID:Identification of nine novel mutations in the Bruton's tyrosine kinase gene in X-linked agammaglobulinaemia patients. 1061 38


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