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

---

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

The families of tyrosine and serine/threonine kinases exhibit shared clusters of conserved amino acid residues. Some conserved residues are confined to the family of tyrosine kinases (TKs), like Tyr at position 1210 in the insulin receptor. Nearly all TKs have at this position Tyr, whereas Ser/Thr kinases generally have Phe at this site. The three-dimensional structure of the insulin receptor TK domain shows Tyr1210 to be located in the cleft, below bound ATP, in a region which potentially contributes to substrate binding. We have examined whether this specific Tyr residue contributes to the generation of TK-specific responses, such as Tyr phosphorylation of Shc, activation of Ras and Erk1,2, and stimulation of DNA synthesis. In addition, we have examined the contribution of Tyr1210 to insulin receptor-specific responses as Tyr phosphorylation of IRS1, stimulation of glycogen synthesis, and dephosphorylation of focal adhesion kinase (FAK). Wild-type and a mutant insulin receptor, in which Tyr1210 was replaced by Phe, were stably expressed in CHO cells, and clones expressing similar numbers of insulin receptors were selected. It was found that replacement of Tyr1210 by Phe resulted in a receptor which was nearly inactive in inducing dephosphorylation of FAK. The mutant receptor was able to induce RasGTP formation, glycogen synthesis, and activation of phosphatidylinositol 3-kinase, though the magnitude of stimulation of some responses was decreased. These findings indicate that Tyr1210 is not essential for the induction of tyrosine kinase-specific responses, such as activation of the Shc/Ras/Erk1,2 pathway and mitogenicity. On the other hand, the abrogation of insulin-induced FAK dephosphorylation indicates that Tyr1210 is involved in coupling of the activated receptor to some downstream targets. Thus, Tyr1210 may fine tune the signal generated by the activated insulin receptor.
...
PMID:Replacement of the conserved tyrosine 1210 by phenylalanine in the insulin receptor affects insulin-induced dephosphorylation of focal adhesion kinase but leaves other responses intact. 875 93

Integrins can trigger signals by activation of cytoplasmic tyrosine kinases, including pp125FAK. Preliminary evidence suggests that serine/threonine kinases such as ERKs may also be activated via integrins. Thus, there seems to be at least partial overlap between RTK signaling pathways and integrin signaling. In tumor cells, ectopic expression or over-expression of certain integrins such as alpha 5/beta 1 can result in reduced tumorigenesis. Presumably the effects of integrins on tumor growth are mediated by the integrin signaling pathway(s) involving FAK and ERKs. However, the precise mechanisms involved have not yet been elucidated.
...
PMID:Integrin signals and tumor growth control. 898 69

Dehydroepiandrosterone sulfotransferase (DHEA ST) catalyzes the sulfation of DHEA and other hydroxysteroids. DHEA ST enzymatic activity in individual human liver biopsy samples has been shown to vary over a five-fold range, and frequency distribution histograms are bimodal, with approximately 25% of subjects included in a high activity subgroup. We set out to characterize the molecular basis for variation in human liver DHEA ST activity. The first step involved performing quantitative Western analysis of cytosol preparations from 92 human liver samples that had been phenotyped with regard to level of DHEA ST enzymatic activity. There was a highly significant correlation (r(s) = 0.635, P < 0.0001) between levels of DHEA ST activity and immunoreactive protein. We next attempted to determine whether the expression of DHEA ST might be controlled, in part, by a genetic polymorphism. DNA was isolated from three "low" and three "high" DHEA ST activity liver samples. Exons and the 5'-flanking region of the DHEA ST gene (STD) were amplified for each of these samples with the polymerase chain reaction (PCR). When compared with "wild type" STD sequence, some of the samples contained a T --> C transition at DHEA ST cDNA nucleotide 170, located within exon 2, resulting in a Met 57 --> Thr change in amino acid. Other samples contained an A --> T transversion at nucleotide 557 within STD exon 4 that resulted in a Glu 186 --> Val change. STD exons 2 and 4 were then sequenced for DNA isolated from an additional 87 liver samples that had been phenotyped with regard to level of DHEA ST enzymatic activity. The allele frequency for the exon 2 polymorphism in these samples was 0.027, whereas that for the exon 4 polymorphism was 0.038, but neither polymorphism was systematically related to the level of enzyme activity in these samples. Transient expression in COS-1 cells of cDNA that contained the nucleotide 170 and 557 polymorphisms, either separately or together, resulted in decreased expression of both DHEA ST enzymatic activity and level of immunoreactive protein, but only when the nucleotide 557 variant was present. Identification of common genetic polymorphisms within STD will now make it possible to test the hypothesis that those polymorphisms might alter in vivo expression and/or function of this important human steroid-metabolizing enzyme.
...
PMID:Human dehydroepiandrosterone sulfotransferase pharmacogenetics: quantitative Western analysis and gene sequence polymorphisms. 901 Mar 52

Pleckstrin homology (PH) domains comprised of loosely conserved sequences of approximately 100 amino acid residues are a functional protein motif found in many signal-transducing and cytoskeletal proteins. We recently demonstrated that the PH domains of Tec family protein-tyrosine kinases Btk and Emt (equal to Itk and Tsk) interact with protein kinase C (PKC) and that PKC down-regulates Btk by phosphorylation. In this study we have characterized the PKC-BtkPH domain interaction in detail. Using pure PKC preparations, it was shown that the Btk PH domain interacts with PKC with high affinity (KD = 39 nM). Unlike other tested phospholipids, phosphatidylinositol 4,5-bisphosphate, which binds to several PH domains, competed with PKC for binding to the PH domain apparently because their binding sites on the amino-terminal portion of the PH domains overlap. The minimal PKC-binding sequence within the Btk PH domain was found to correspond roughly to the second and third beta-sheets of the PH domains of known tertiary structures. On the other hand, the C1 regulatory region of PKCepsilon containing the pseudosubstrate and zinc finger-like sequences was found to be sufficient for strong binding to the Btk PH domain. Phorbol 12-myristate 13-acetate (PMA), a potent activator of PKC that interacts with the C1 region of PKC, inhibited the PKC-PH domain interaction, whereas the bioinactive PMA (4-alpha-PMA) was ineffective. The zeta isoform of PKC, which has a single zinc finger-like motif instead of the two tandem zinc finger-like sequences present in conventional and novel PKC isoforms, does not bind PMA. Thus, as expected, PH domain binding with PKCzeta was not interfered with by PMA. Further, inhibitors that are known to attack the catalytic domains of serine/threonine kinases did not affect this PKC-PH domain interaction. In contrast, the presence of physiological concentrations of Ca2+ induced less than a 2-fold increase in PKC-PH domain binding. These results indicate that PKC binding to PH domains involve the beta2-beta3 region of the Btk PH domain and the C1 region of PKC, and agents that interact with either of these regions (i.e. phosphatidylinositol 4,5-bisphosphate binding to the PH domain and PMA binding to the C1 region of PKC) might act to regulate PKC-PH domain binding.
...
PMID:Interactions between protein kinase C and pleckstrin homology domains. Inhibition by phosphatidylinositol 4,5-bisphosphate and phorbol 12-myristate 13-acetate. 914 13

Growth hormone (GH) rapidly stimulates tyrosine phosphorylation followed by serine/threonine phosphorylation of multiple cytoplasmic STAT transcription factors, including one, STAT5b, that is uniquely responsive to the temporal pattern of plasma GH stimulation in rat liver and is proposed to play a central role in the activation of male-expressed liver genes by GH pulses in vivo (Waxman, D. J., Ram, P. A., Park, S. H., and Choi, H. K. (1995) J. Biol. Chem. 270, 13262-13270). We now show that JAK2, the GH receptor-associated tyrosine kinase, is present both in the cytosol and in the nucleus in cultured liver cells and in rat liver in vivo and that GH-activated STAT3 but not STAT5b becomes associated with nuclear JAK2. GH is also shown to activate by 3-4-fold SHP-1, a phosphotyrosine phosphatase that contains two src homology 2 (SH2) domains. GH also induces nuclear translocation and binding of SHP-1 to tyrosine-phosphorylated STAT5b, suggesting that this GH-activated phosphatase may play a role in dephosphorylation leading to deactivation of nuclear STAT5b following the termination of a plasma GH pulse in male rat liver in vivo. No such association of SHP-1 with GH-activated STAT3 was detected, a finding that could help explain the marked desensitization of STAT3, but not STAT5b, to subsequent GH pulses following an initial GH activation event.
...
PMID:Interaction of growth hormone-activated STATs with SH2-containing phosphotyrosine phosphatase SHP-1 and nuclear JAK2 tyrosine kinase. 921 20

Myosin light chain (MLC) phosphorylation catalyzed by the Ca(2+)- calmodulin-dependent MLC kinase (MLCK) is critical to thrombin-mediated endothelial cell gap formation and barrier dysfunction. We have tested the hypothesis that the Ca2+ ionophore ionomycin stimulates MLCK-dependent endothelial cell contraction and permeability. Ionomycin significantly increased albumin clearance and decreased electrical resistance across confluent bovine pulmonary microvascular and macrovascular endothelial cell monolayers in a concentration-dependent manner that was temporally similar to that produced by thrombin. In contrast, however, ionomycin produced a significant Ca(2+)-dependent reduction in the levels of phosphorylated MLC with evidence of serine/threonine phosphatase activation. Potential MLCK-independent mechanisms of endothelial cell permeability were examined with little evidence to support a role for stimulated nitric oxide synthase or phospholipase A2 activities. Importantly, ionomycin produced 1) reductions in the activities of the barrier protective adenylate cyclase and the adenosine 3',5'-cyclic monophosphate-dependent protein kinase A, 2) dramatic dose- and time-dependent inhibition of endothelial cell tyrosine kinase activities, and 3) marked decreases in the phosphotyrosine content of the p125 focal adhesion kinase. These data indicate that ionomycin produces endothelial cell barrier dysfunction by mechanisms that are independent of MLCK activation and may involve reductions in endothelial cell tethering forces via inhibition of protein kinase A and tyrosine kinase activities, especially the p125 focal adhesion kinase.
...
PMID:Mechanisms of ionomycin-induced endothelial cell barrier dysfunction. 925 54

Locomotion of T lymphocytes within three-dimensional collagen matrices is regulated via different signaling states of the cells. Purified human CD4+ and CD8+ T cells developed a spontaneously locomoting subpopulation of about 25% of the whole population immediately after incorporation into a three-dimensional collagen matrix analyzed by time-lapse videomicroscopy. This spontaneous locomotion was accompanied by enhanced tyrosine phosphorylation of the focal adhesion kinase (FAK). Inhibition of protein tyrosine kinase (PTK) activity using genistein significantly reduced the spontaneous locomotory activity. This reduction was overcome by subsequent activation of protein kinase C (PKC) using PMA, which led to a persistent increase of locomotory activity to more than 60% of the cells. Thus, the PKC-driven type of locomotion was independent of PTK activity, whereas spontaneous locomotion was not altered by inhibition of PKC activity using calphostin C or inhibition of the serine/ threonine phosphatases pp1 and pp2A using okadaic acid. We presume that PTK activity, especially tyrosine phosphorylation of FAK, is decisively involved in the regulation of spontaneous T lymphocyte locomotion, which is independent of PKC activity. In contrast, PKC-driven locomotion is independent of tyrosine phosphorylation events, indicating that T lymphocyte locomotion is regulated by more than one signal transduction pathway. Furthermore, confocal microscopy analysis of phosphotyrosine residues, FAK, and PKC revealed an exclusive cellular distribution of these components, suggesting a regulation of T lymphocyte locomotion different from migration models developed for other cell types, which refer to a colocalization of FAK and PKC in focal adhesions.
...
PMID:Differential requirement of protein tyrosine kinases and protein kinase C in the regulation of T cell locomotion in three-dimensional collagen matrices. 931 18

293 cells were transfected with wild-type GSK3beta (WT-GSK3beta) or a mutant in which the PKB phosphorylation site (Ser-9) was altered to Ala (A9-GSK3beta). Upon stimulation with IGF-1 or insulin, WT-GSK3beta was inhibited 75% or 60%, respectively, whereas the activity of the A9-GSK3beta mutant was unaffected. Incubation of WT-GSK3beta with PP2A1 (a Ser/Thr-specific phosphatase) completely reversed the IGF-1- or insulin-induced inhibition. IGF-1 stimulation did not induce any tyrosine dephosphorylation of WT-GSK3beta or A9-GSK3beta. Coexpression of WT-GSK3beta in 293 cells with either PKB alpha (also known as AKT) or PDK1 (the 'upstream' activator of PKB) mimicked the IGF-1- or insulin-induced phosphorylation of Ser-9 and inactivation of GSK3beta.
...
PMID:Further evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 and not by dephosphorylation of Tyr-216. 937 75

Four Holstein steers (159 kg) surgically fitted with abomasal-infusion cannulas were used in a 4 x 4 Latin square study to test amino acid (AA) and casein (CAS) infusions on nitrogen balance and hormonal status of steers consuming vegetative wheat (Triticum aestivum L.) silage (12.3% CP). Treatments were 5-d infusions of 1) water (CONT), 2) arginine (ARG; 13.69 g/d), 3) limiting amino acids (LAA, 13.69 g/d arginine + 10.92 g/d histidine + 28.97 g/d lysine + 10.88 g/d methionine + 16.96 g/d threonine, and 4) Na-CAS (300 g/d). Whole blood was collected for plasma AA, growth hormone (GH), insulin, and IGF-I concentrations. Data were analyzed by ANOVA, and the following orthogonal contrasts were used to separate treatment means: CONT vs ARG; ARG vs LAA; and LAA vs CAS. Urinary N increased (P < .02) for CAS vs LAA. Arginine increased N retention, as did CAS, compared to LAA. Total plasma essential AA were decreased by arginine. Mean plasma insulin concentrations were increased by CAS (P < .034). Arginine increased mean plasma GH levels, but not IGF-I. The CAS treatment increased (P < .015) IGF-I levels, but not GH. These data suggest that performance of steers fed wheat silage was limited by duodenal AA flow and that arginine was the first-limiting AA. Casein infusion increased plasma insulin and IGF-I, which would explain the improved growth noted in calves and lambs fed forages supplemented with ruminally undegraded protein.
...
PMID:Nitrogen metabolism and hormonal responses of steers fed wheat silage and infused with amino acids or casein. 937 20

The tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), acutely stimulates the tyrosine phosphorylation of proteins of approximately 190, 120, and 70 kDa in the well differentiated Fao rat hepatoma cell line. This phosphorylation is dependent on protein kinase C (PKC) and is abolished by down-regulation of PKC or pretreatment with a PKC inhibitor. Purification of the 190-kDa tyrosine-phosphorylated protein revealed that it consists of both ErbB2 and ErbB3. Following PMA-induced tyrosine phosphorylation, ErbB2 and ErbB3 were able to associate with the SH2 domains of several signaling proteins including the p85alpha subunit of phosphatidylinositol 3-kinase, Syp, and Grb2. The 120-kDa protein phosphorylated in response to PMA consists of at least two proteins: focal adhesion kinase that exhibits a minor increase in tyrosine phosphorylation following treatment with PMA, and a major 120-kDa tyrosine-phosphorylated species in PMA-stimulated Fao cells which as yet is unidentified. Similarly, the 70-kDa tyrosine-phosphorylated protein also appears to represent more than one protein, including paxillin and a second protein of similar mobility which appears to be the major tyrosine phosphorylation in response to PMA. Both ErbB2 and paxillin also exhibit reduced migration on SDS-polyacrylamide gel electrophoresis following PMA treatment, suggesting that they are also phosphorylated on serine/threonine residues. The mobility shift of both of these proteins is abolished by treatment with inhibitors of PKC or mitogen-activated protein kinase/extracellular signal-related kinase kinase. These results suggest a novel mechanism of cross-talk between the serine/threonine kinase PKC and tyrosine phosphorylation pathways. The activation of ErbB2 and ErbB3 that is initiated by PMA may contribute to the tumor promoting activity of these compounds.
...
PMID:Cross-talk between phorbol ester-mediated signaling and tyrosine kinase proto-oncogenes. I. Activation of protein kinase C stimulates tyrosine phosphorylation and activation of ErbB2 and ErbB3. 938 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---