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 immediate early gene NUR77 (also called NGFI-B) is required for T cell antigen receptor-mediated cell death and is induced to very high levels in immature thymocytes and T cell hybridomas undergoing apoptosis. The Akt (PKB) kinase is a key player in transduction of anti-apoptotic and proliferative signals in T cells. Because Nur77 has a putative Akt phosphorylation site at Ser-350, and phosphorylation of this residue is critical for the transactivation activity of Nur77, we investigated whether Akt regulates Nur77. Coimmunoprecipitation experiments showed the detection of Nur77 in Akt immune complexes, suggesting that Nur77 and Akt physically interact. We further show that Akt specifically phosphorylates Ser-350 of the Nur77 protein within its DNA-binding domain in vitro and in vivo in 293 and NIH 3T3 cells. Because phosphorylation of Ser-350 of Nur77 is critical for its function as a transcription factor, we examined the effect of Akt on this function. By using luciferase assay experiments, we showed that phosphorylation of Nur77 by Akt decreased the transcriptional activity of Nur77 by 50--85%. Thus, we show that Akt interacts with Nur77 and inactivates Nur77 by phosphorylation at Ser-350 in a phosphatidylinositol 3-kinase-dependent manner, connecting the phosphatidylinositol 3-kinase-dependent Akt pathway and a nuclear receptor pathway.
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PMID:Akt phosphorylates and regulates the orphan nuclear receptor Nur77. 1127 86

Arginine-mediated regulation is remarkably well conserved in very divergent bacteria, and shows a number of unusual features that distinguish arginine regulation from other transcriptional control mechanisms. The arginine repressor subunit consists of a basic N-terminal DNA-binding domain, which belongs to the winged helix-turn-helix family, connected through a flexible linker to an acidic C-terminal domain responsible for binding of arginine and assembly of the high-affinity holohexamer, which binds an approximately 40 bp target. To gain further insight into the molecular details of arginine repressor-operator interactions we have established a high resolution contact map of the argC operator from Bacillus stearothermophilus, a moderate thermophilic Gram-positive bacterium, and the argR operator from Thermotoga neapolitana, a Gram-negative hyperthermophile, with the corresponding ArgR proteins. Enzymatic and chemical footprinting have been combined with missing contact, pre-modification, base substitution, and small ligand binding interference techniques to gather information on backbone and base-specific contacts with major and minor groove determinants of the operators. Wild-type and mutant argC operators have been compared for their interaction with the repressor, using both in vivo and in vitro approaches. Our results indicate that the operators of B. stearothermophilus and T. neapolitana consist of two ARG box-like sequences, 18 bp imperfect palindromes, separated by two and three base-pairs, respectively, and that the repressors from thermophilic origin establish base-specific contacts with two major groove segments and the intervening minor groove of each ARG box, all aligned on one face of the helix. In contrast, no specific contacts are established in the minor groove facing the repressor in the centre of the operator, nevertheless this region plays a crucial structural role in complex formation, as indicated by mutant studies. This picture is reminiscent of arginine repressor binding in Escherichia coli, and therefore reinforces the uniform view of arginine regulation, but also reveals a number of striking differences at particular positions of the boxes and in the length and base-pair composition of the spacer connecting two ARG boxes in the operator. These might be responsible, in part, for subtle but important functional and mechanistic differences in the way species-specific repressors interact with their cognate target sites. These variations are underlined by the different behaviour of the repressors from E. coli, B. stearothermophilus and T. neapolitana in their potential to bind heterologous operators, their requirement for arginine, and the resistance of complex formation to non-specific competitor DNA. Our findings are discussed in view of the crystal structure of the arginine repressor from B. stearothermophilus.
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PMID:Transcription regulation in thermophilic bacteria: high resolution contact probing of Bacillus stearothermophilus and Thermotoga neapolitana arginine repressor-operator interactions. 1178 10

Prolactin (PRL) interacts with a single-chain prolactin-specific receptor of the cytokine receptor superfamily. PRL triggers the activation of JAK2 kinase, which phosphorylates the PRL receptor itself, and of STAT5, a member of the family of signal transducers and activators of transcription (STAT). We have shown that the STAT5-dependent immediate early gene, CIS1 (Cytokine-Inducible SH2 domain-containing protein-1), suppresses PRL-induced STAT5 activation in vitro as well as in transgenic mice. To facilitate the study of the interactions between CIS1 and the PRL receptor, we have developed the yeast tri-hybrid system, a modification of the yeast two-hybrid system. We expressed CIS1 fused to the DNA-binding domain and PRL receptor cytoplasmic domain fused to the transcription activation domain in the presence or absence of the tyrosine kinase domain of JAK2 in yeast. CIS1 bound to the PRL receptor cytoplasmic domain in a JAK2-dependent manner. Moreover, we determined that the phosphorylated Y532 of the murine PRL receptor is the binding site for CIS1. Interestingly, Y532 has been shown to be unnecessary for STAT5 activation, although CIS1 overexpression suppressed PRL-induced STAT5 activation. These data suggest that the suppression of STAT5 activation by CIS1 is not due to a simple competition with STAT5 but rather to a modification of the receptor by CIS1 binding.
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PMID:CIS1 interacts with the Y532 of the prolactin receptor and suppresses prolactin-dependent STAT5 activation. 1276 Dec 5

Modulators of cofactor recruitment by nuclear receptors are expected to play an important role in the coordination of hormone-induced transactivation processes. To identify such factors interacting with the N-terminal domain (NTD) of the progesterone receptor (PR), we used this domain as bait in the yeast Sos-Ras two-hybrid system. cDNAs encoding the C-terminal MYST (MOZ-Ybf2/Sas3-Sas2-Tip60 acetyltransferases) domain of HBO1 [histone acetyltransferase binding to the origin recognition complex (ORC) 1 subunit], a member of the MYST acetylase family, were thus selected from a human testis cDNA library. In transiently transfected CV1 cells, the wild-type HBO1 [611 amino acids (aa)] enhanced transcription mediated by steroid receptors, notably PR, mineralocorticoid receptor, and glucocorticoid receptor, and strongly induced PR and estrogen receptor coactivation by steroid receptor coactivator 1a (SRC-1a). As assessed by two-hybrid and glutathione-S-transferase pull-down assays, the HBO1 MYST acetylase domain (aa 340-611) interacts mainly with the NTD, and also contacts the DNA-binding domain and the hinge domains of hormone-bound PR. The HBO1 N-terminal region (aa 1-340) associates additionally with PR ligand-binding domain (LBD). HBO1 was found also to interact through its NTD with SRC-1a in the absence of steroid receptor. The latter coassociation enhanced specifically activation function 2 activation function encompassed in the LBD. Conversely, the MYST acetylase domain specifically enhanced SRC-1 coupling with PR NTD, through a hormone-dependent mechanism. In human embryonic kidney 293 cells expressing human PRA or PRB, HBO1 raised selectively an SRC-1-dependent response of PRB but failed to regulate PRA activity. We show that HBO1 acts through modification of an LBD-controlled structure present in the N terminus of PRB leading to the modulation of SRC-1 functional coupling with activation function 3-mediated transcription. Importantly, real-time RT-PCR analysis also revealed that HBO1 enhanced SRC-1 coactivation of PR-dependent transcription of human endogenous genes such as alpha-6 integrin and 11beta-hydroxydehydrogenase 2 but not that of amphiregulin. Immunofluorescence and confocal microscopy of human embryonic kidney-PRB cells demonstrated that the hormone induces the colocalization of HBO1 with PR-SRC-1 complex into nuclear speckles characteristic of PR-mediated chromatin remodeling. Our results suggest that HBO1 might play an important physiological role in human PR signaling.
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PMID:Ligand-controlled interaction of histone acetyltransferase binding to ORC-1 (HBO1) with the N-terminal transactivating domain of progesterone receptor induces steroid receptor coactivator 1-dependent coactivation of transcription. 1664 42

Tumour-specific chromosomal rearrangements are known to create chimaeric products with the ability to generate many human cancers. hTAF(II)68-TEC (where hTAF(II)68 is human TATA-binding protein-associated factor II 68 and TEC is translocated in extraskeletal chondrosarcoma) is such a fusion product, resulting from a t(9;17) chromosomal translocation found in extraskeletal myxoid chondrosarcomas, where the hTAF(II)68 NTD (N-terminal domain) is fused to TEC protein. To identify proteins that control hTAF(II)68-TEC function, we used affinity chromatography on immobilized hTAF(II)68 (NTD) and MALDI-TOF (matrix-assisted laser-desorption ionization-time-of-flight) MS and isolated a novel hTAF(II)68-TEC-interacting protein, GAPDH (glyceraldehyde-3-phosphate dehydrogenase). GAPDH is a glycolytic enzyme that is also involved in the early steps of apoptosis, nuclear tRNA export, DNA replication, DNA repair and transcription. hTAF(II)68-TEC and GAPDH were co-immunoprecipitated from cell extracts, and glutathione S-transferase pull-down assays revealed that the C-terminus of hTAF(II)68 (NTD) was required for interaction with GAPDH. In addition, three independent regions of GAPDH (amino acids 1-66, 67-160 and 160-248) were involved in binding to hTAF(II)68 (NTD). hTAF(II)68-TEC-dependent transcription was enhanced by GAPDH, but not by a GAPDH mutant defective in hTAF(II)68-TEC binding. Moreover, a fusion of GAPDH with the GAL4 DNA-binding domain increased the promoter activity of a reporter containing GAL4 DNA-binding sites, demonstrating the presence of a transactivation domain(s) in GAPDH. The results of the present study suggest that the transactivation potential of the hTAF(II)68-TEC oncogene product is positively modulated by GAPDH.
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PMID:Regulation of oncogenic transcription factor hTAF(II)68-TEC activity by human glyceraldehyde-3-phosphate dehydrogenase (GAPDH). 1730 60

Attenuation of the p53 protein is one of the most common abnormalities in human tumors. Another important marker of tumorigenesis is focal adhesion kinase (FAK), a 125-kDa tyrosine kinase that is overexpressed at the mRNA and protein levels in a variety of human tumors. FAK is a critical regulator of adhesion, motility, metastasis, and survival signaling. We have characterized the FAK promoter and demonstrated that p53 can inhibit the FAK promoter activity in vitro. In the present study, we showed that p53 can bind the FAK promoter-chromatin region in vivo by chromatin immunoprecipitation (ChIP) assay. Furthermore, we demonstrated down-regulation of FAK mRNA and protein levels by adenoviral overexpression of p53. We introduced plasmids with different mutations in the DNA-binding domain of p53 (R175H, p53 R248W and R273H) into HCTp53(-/-) cells and showed that these mutations of p53 did not bind FAK promoter and did not inhibit FAK promoter activity, unlike wild type p53. We analyzed primary breast and colon cancers for p53 mutations and FAK expression, and showed that FAK expression was increased in tumors containing mutations of p53 compared to tumors with wild type p53. In addition, tumor-derived missense mutations in the DNA-binding domain (R282, R249, and V173) also led to increased FAK promoter activity. Thus, the present data show that p53 can regulate FAK expression during tumorigenesis.
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PMID:p53 regulates FAK expression in human tumor cells. 1799 88

In Bacillus subtilis the concentration of L-arginine is controlled by the transcriptional regulator AhrC, which interacts with 18 bp DNA operator sites called ARG boxes in the promoters of arginine biosynthetic and catabolic operons. AhrC is a 100 kDa homohexamer, with each subunit having two domains. The C-terminal domains form the core, mediating intersubunit interactions and binding of the co-repressor L-arginine, whilst the N-terminal domains contain a winged helix-turn-helix DNA-binding motif and are arranged around the periphery. The N-terminal domain of AhrC has been expressed, purified and characterized and it has been shown that the fragment still binds DNA operators as a recombinant monomer. The DNA-binding domain has also been crystallized and the crystal structure refined to 1.0 A resolution is presented.
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PMID:A high-resolution structure of the DNA-binding domain of AhrC, the arginine repressor/activator protein from Bacillus subtilis. 1800 39

Identifying genetic pathways that cooperate in leukemogenesis facilitates our understanding of the molecular mechanisms at play. Interferon consensus sequence-binding protein (ICSBP) is a tumor suppressor, whose downregulation cooperates with BCR-ABL and NUP98-TOP1 gene products to accelerate leukemia induction in mouse models. Similarly, Meis1 synergizes with HoxA9 or NUP98-HOX (but not NUP98-TOP1) fusion genes to promote the early onset of leukemia. To investigate whether Icsbp deficiency interacts with Meis1 or its family member Meis3, we transplanted Icsbp(-/-) bone marrow (BM) cells after transduction with Meis1 or Meis3 retroviral vectors. Here, we show that enforced expression of Meis1 or Meis3 in Icsbp(-/-) BM cells induces a fatal, invasive myeloproliferative disease. Secondary mutations, such as activation of Mn1, led to the progression to acute myeloid leukemia in a few mice. Interestingly, expression of endogenous Meis1 and Meis3 mRNAs was repressed in the granulocytic progenitor population of Icsbp(-/-) mice. These results reveal a novel collaboration between Icsbp deficiency and Meis1/Meis3 in the acceleration of chronic myeloid leukemia-like disease.
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PMID:Acceleration of chronic myeloproliferation by enforced expression of Meis1 or Meis3 in Icsbp-deficient bone marrow cells. 1822 76

Evidence is emerging that estrogen receptor alpha (ERalpha) is central to the rapid transduction of estrogen signaling to the downstream kinase cascades; however, the mechanisms underlying this nongenomic function are not fully understood. Here we report a paradigm of ERalpha regulation through arginine methylation by PRMT1, which transiently methylates arginine 260 within the ERalpha DNA-binding domain. This methylation event is required for mediating the extranuclear function of the receptor by triggering its interaction with the p85 subunit of PI3K and Src. Furthermore, we find that the focal adhesion kinase (FAK), a Src substrate involved in the migration process, is also recruited in this complex. Our data indicate that the methylation of ERalpha is a physiological process occurring in the cytoplasm of normal and malignant epithelial breast cells and that ERalpha is hypermethylated in a subset of breast cancers.
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PMID:Regulation of estrogen rapid signaling through arginine methylation by PRMT1. 1865 4

Ikaros is a zinc-finger transcriptional factor playing an essential role in lymphoid lineage commitment and differentiation. Animal models and analysis of human Ikaros in leukemic cells demonstrate deregulation of Ikaros expression. Short isoforms with a truncated DNA-binding domain suppress functions of Ikaros in a dominant-negative manner. Previous studies demonstrated that human leukemias are heterogeneous for Ikaros expression. We estimate the relative level of Ikaros mRNA transcripts in 80 childhood ALL cases in comparison with AML and healthy donor groups. We detected eight major isoforms and several minor mutant isoforms in most patients with acute lymphoblastic and myeloid leukemia and in healthy donors, but the relative level of expression varied. The relatively high level of Ik4A isoform, rarely mentioned in previous reports, was detected in all analyzed groups. The ratio between functional and all isoforms was used to determine functional activity of Ikaros. The ratio was significantly less in AML (p=0.027) and BCR-ABL positive ALL (p=0.0028) than in healthy bone marrow. We found a negative association between the Ikaros ratio and myeloid coexpression in B-cell ALL, the most prominent was for CD15. The Ikaros ratio positively correlates with CD5 and negatively with CD7 expression in T-ALL. We suggest that an anti-proliferation and anti-activation effect of full-length Ikaros may be mediated through regulation of CD5 and CD7.
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PMID:Relative expression of different Ikaros isoforms in childhood acute leukemia. 1867 65


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