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)

When DeLalla and Gofman (1954) presented their work "Ultracentrifugal Analysis of Serum Lipoproteins" more than 25 years ago, we were thinking about lipoproteins in terms of density fractions. In the 1970s the electrophoresis concept was pushed by Fredrickson and his colleagues (Fredrickson et al., 1967). There is no doubt that both these lipoprotein research centers have fertilized entire investigations in this field and still have a tremendous impact on our current knowledge. It was, however, not until 1966, when Gustafson, Alaupovic, and Furmann first described the presence of a third lipoprotein family, LpC, that researchers in this area became aware of the dominant role of apolipoproteins in the transport and metabolism of plasma lipids. Lipoprotein density fractions and electrophoretic classes in the mean time have not lost their importance; they still exist and the application of methods yielding those fractions is still going on in lipoprotein laboratories. Yet we need to recognize that the whole lipid transport system is far more complex than was believed some 10 or 20 years ago. Lipoprotein density fractions consist of varying numbers of families; some of them comigrate upon electrophoresis, and the protein moiety of them is mostly composed of nonidentical polypeptides. There are a number of inborn errors of metabolism, for example, ABL, Tangier disease, and enzyme defects, which have taught us a lot about the functions and interplay of the complex apolipoprotein system. In dyslipoproteinemia, abnormal lipoproteins occur in the plasma and apolipoproteins, which are hardly recognized in normal fasting plasma, suddenly become prominent. There still exist, however, apolipoproteins and lipoproteins, one of which certainly is Lp(a), whose function and biological significance remains completely unknown. The structure and the molecular arrangement of lipids and apolipoproteins within a lipoprotein particle has been the subject of intensive investigations, and almost every physicochemical method available has been applied to reveal the morphology of individual lipoproteins in closest detail. Lipoproteins and apolipoproteins have often also served as model substances for cell membranes. After the purification of individual apolipoproteins succeeded in many laboratories and specific antibodies were available, clinical chemists and epidemiologists became interested in this area of research. Apolipoprotein quantification currently is most prominent for the prediction of atherosclerotic risk in preventive medicine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Apolipoproteins and lipoproteins of human plasma: significance in health and in disease. 623 Sep

The growth hormone receptor (GHR) belongs to the superfamily of transmembrane proteins that includes the prolactin receptor and a number of cytokine receptors. Two forms exist for the GHR: the full-length membrane-bound human receptor is a protein of 620 amino acids with a single transmembrane region; and the GH binding protein (GHBP) is a short soluble from corresponding to the extracellular domain of the full-length receptor. In rodents, GHBP is encoded by a specific mRNA of 1.2-1.5 kb, whereas in man and other species GHBP is believed to result from proteolytic cleavage of the membrane receptor. Growth hormone binding protein prolongs the half-life of GH but other functions for GHBP remain to be demonstrated. Recombinant GHBP complexed to human GH shows a 2:1 stoichiometric crystal structure. Growth hormone-induced dimerization of the cell surface GHR appears to be a prerequisite for biological activity of the hormone. JAK2 has been identified as a tyrosine kinase associated with GHR and other receptors of the superfamily. Binding of GH to its receptor results in dimerization of the GHR, phosphorylation of JAK2 and of the GHR. Other substrates for JAK2 have to be identified. Transcription factors belonging to the STAT (signal transducers and activators of transcriptions) family are involved in the transcriptional effects of GH. The activity of mutants of the GHR has been measured in functional tests to identify sequences of the cytoplasmic domain of the receptor that are important for signal transduction. A proline-rich sequence, called Box I, conserved among members of the receptor family has been shown to be crucial for GH effects on gene transcription. MAP kinase activity and cell proliferation. The C-terminal region of the GHR is required for tyrosine phosphorylation of the receptor and for a hormonal effect on gene transcription, whereas only 46 membrane proximal amino acids of the cytoplasmic domain are necessary for activation of JAK2 and transduction of the GH proliferative signal. Much work remains to be done to identify other protein kinases and signalling molecules involved in the mechanism of action of GH.
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PMID:Growth hormone receptor: structure and signal transduction. 854 48

The growth hormone (GH) receptor belongs to the superfamily of transmembrane proteins that includes the prolactin (PRL) receptor and a number of cytokine receptors. Two forms exist for the GH receptor: the membrane-bound form is a protein of 620 amino acid residues with a unique transmembrane domain; the GH-binding protein (GHBP), which is a soluble short form, is identical to the extracellular domain of the membrane receptor. In man and many other species, GHBP is believed to result from proteolytic cleavage of the membrane receptor; in human tissues, only one mRNA form of 4.5 kb encoding the full-length receptor has been detected. In rodents, GHBP is encoded by a specific mRNA of 1.2kb. Binding of GH to its receptor results in dimerization of the receptor, phosphorylation of the tyrosine kinase JAK2 and of the receptor, followed by a cascade of protein phosphorylations. Transcription factors belonging to the signal transducers and activators of transcription (STAT) family are involved in the effects of GH on the transcription of genes such as c-fos, serine protease inhibitor Spi 2.1 and beta-casein. GH is able to activate several STAT proteins including STAT1, 3 and 5. The JAK-STAT pathway is a main pathway for GH effects on gene transcription. Other signalling molecules are involved in GH action through different pathways: GH is able to activate mitogen activated protein (MAP) kinases; the hormone can utilize insulin receptor substrate-1 (IRS-1) and induces the association of phosphatidylinositol 3-kinase with IRS-1. Two main functional regions have been defined in the cytoplasmic domain of the GH receptor by testing the activity of mutant forms of the receptor in several systems: Box 1, a proline-rich sequence in the membrane proximal part, is necessary for all GH effects and is probably the region of association with JAK2; the C-terminal region is required for the induction of specific genes. Other molecules involved in the mechanisms of action of GH remain to be identified. As the same signalling pathways are used by many ligands, explanations for the specificity of the cellular effects have to be determined.
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PMID:Growth hormone receptor signalling. 885 42

It has been assumed that membrane-bound glycosyltransferases function within the Golgi apparatus to glycosylate glycoproteins. We now report, however, that a truncated, soluble recombinant form of the murine alpha1,3-galactosyltransferase expressed in human 293 cells is highly efficient and comparable to the full-length enzyme in alpha-galactosylating both newly synthesized membrane-associated and secreted glycoproteins. Although the soluble enzyme was secreted by cells as expected, we also found that the full-length, membrane-associated form was secreted. Unexpectedly, both secreted forms are cleaved identically at two primary sites within the stem region by endogenous protease(s) at the indicated positions in the sequence 73KDWW (downward arrow) FPS (downward arrow) WFKNG. These results demonstrate that the soluble alpha1,3-galactosyltransferase is functional within the cell and that specific proteolysis occurs in the stem region. The widespread occurrence of different soluble glycosyltransferases secreted by cells suggests that normal glycoconjugate biosynthesis may involve cooperation between membrane-bound and soluble enzymes.
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PMID:A soluble form of alpha1,3-galactosyltransferase functions within cells to galactosylate glycoproteins. 915 11

Nonobese diabetic (NOD) mouse thymocytes are hyporesponsive to T cell antigen receptor (TCR)-mediated stimulation of proliferation, and this T cell hyporesponsiveness may be causal to the onset of autoimmune diabetes in NOD mice. We previously showed that TCR-induced NOD T cell hyporesponsiveness is associated with a block in Ras activation and defective signaling along the PKC/Ras/MAPK pathway. Here, we report that several sequential changes in TCR-proximal signaling events may mediate this block in Ras activation. We demonstrate that NOD T cell hyporesponsiveness is associated with the (a) enhanced TCR-beta-associated Fyn kinase activity and the differential activation of the Fyn-TCR-zeta-Cbl pathway, which may account for the impaired recruitment of ZAP70 to membrane-bound TCR-zeta; (b) relative inability of the murine son of sevenless (mSOS) Ras GDP releasing factor activity to translocate from the cytoplasm to the plasma membrane; and (c) exclusion of mSOS and PLC-gamma1 from the TCR-zeta-associated Grb2/pp36-38/ZAP70 signaling complex. Our data suggest that altered tyrosine phosphorylation and targeting of the Grb2/pp36-38/ZAP70 complex to the plasma membrane and cytoskeleton and the deficient association of mSOS with this Grb2-containing complex may block the downstream activation of Ras and Ras-mediated amplification of TCR/CD3-mediated signals in hyporesponsive NOD T cells. These findings implicate mSOS as an important mediator of downregulation of Ras signaling in hyporesponsive NOD T cells.
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PMID:Impaired plasma membrane targeting of Grb2-murine son of sevenless (mSOS) complex and differential activation of the Fyn-T cell receptor (TCR)-zeta-Cbl pathway mediate T cell hyporesponsiveness in autoimmune nonobese diabetic mice. 929 43

Signaling by the antigen receptor of T lymphocytes initiates different developmental transitions, each of which require the tyrosine kinase ZAP70. Previous studies with agonist and antagonist peptides have indicated that ZAP70 might respond differently to different structures of the TCR-CD3 complex induced by bound peptides. The roles of membrane proximity and orientation in activation of ZAP70 signaling were explored using synthetic ligands and their binding proteins designed to produce different architectures of membrane-bound complexes composed of ZAP70 fusion proteins. Transient membrane recruitment of physiological levels of ZAP70 with the membrane-permeable synthetic ligand FK1012A leads to rapid phosphorylation of ZAP70 and activation of the ras/MAPK and Ca2+/calcineurin signaling pathways. ZAP70 SH2 domains are not required for signaling when the kinase is artifically recruited to the membrane, indicating that the SH2 domains function solely in recruitment and not in kinase activation. Using additional synthetic ligands and their binding proteins that recruit ZAP70 equally well but orient it at the cell membrane in different ways, we define a requirement for a specific presentation of ZAP70 to its downstream targets. These results provide a mechanism by which ZAP70, bound to the phosphorylated receptor, could discriminate between conformational changes induced by the binding of different MHC-peptide complexes to the antigen receptor and introduce an approach to exploring the role of spatial orientation of signaling complexes in living cells.
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PMID:Proximity and orientation underlie signaling by the non-receptor tyrosine kinase ZAP70. 931 21

Studies on the role of interleukin-6 (IL-6) in bone metabolism have been accumulating. However, its effects on osteoblasts are still unclear because the results are conflicting depending on the study models employed. We reasoned that these conflicting data are due to variable expression levels of membrane-bound IL-6 receptors (IL-6Rs). In the present study, we found that IL-6 in combination with soluble IL-6R (sIL-6R) consistently caused a marked elevation of alkaline phosphatase and a decrease in proliferation in the human osteoblastic cell line MG-63, which expressed no detectable membrane-bound IL-6R and failed to respond to IL-6. These effects of IL-6/sIL-6R were blocked by neutralizing antibodies to the IL-6 signal transducer gp130, suggesting an involvement of IL-6 signaling in the elicitation of the effects of IL-6/sIL-6R. Upon stimulation with IL-6/sIL-6R, the gp130, cytoplasmic Janus kinases JAK1 and JAK2 were tyrosine phosphorylated. Moreover, signal transducers and activators of transcription STAT1 and STAT3 were also tyrosine phosphorylated, translocated to the nucleus, and bound to the putative STAT-binding DNA elements. In addition, mitogen-activated protein (MAP) kinase was also activated in response to IL-6/sIL-6R These data demonstrate that sIL-6R may enhance the responsiveness of MG-63 cells to IL-6. Thus, IL-6 in collaboration with sIL-6R may modulate differentiation and proliferation of osteoblastic cells, presumably by activating two distinct signaling pathways of JAK-STAT and MAP kinase.
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PMID:Combination of interleukin-6 and soluble interleukin-6 receptors induces differentiation and activation of JAK-STAT and MAP kinase pathways in MG-63 human osteoblastic cells. 961 Jul 41

Many soluble factors of neural, endocrine, paracrine and autocrine origin are present in the thymus and modulate its function. Long-term effects of sex steroids have been documented for thymocytes and cells of the thymic microenvironment. In this report we examine rapid actions of progesterone upon aspects of epithelial cell physiology. Progesterone (0.1-10 microM) was applied to cultured thymulin-secreting thymic epithelial cells (TS-TEC) and changes in transmembrane potential, transmembrane current, intracellular calcium levels and thymulin secretion were assessed. Rapid changes in electrophysiology and intracellular calcium provide evidence for a membrane-bound progesterone receptor in these cells, in addition to classical cytoplasmic receptors. Application of progesterone to TS-TEC caused electrophysiological changes in 56% of cells (n = 40), activating an inward current (-24 +/- 9 pA at 1 microM, n = 7, p < 0.02) and dose-dependent depolarization (7.1 +/- 1.8 mV at 1 microM, n = 19, p < 0.01). Intracellular calcium levels, monitored by the ratiometric fluorescent calcium indicator fura-2, increased within seconds of progesterone (1 microM) application. Progesterone (1 microM) increased thymulin levels in supernatant, as measured by ELISA, above the levels in the preapplication period (142 +/- 16% of the preapplication period, n = 3, p < 0.02). This effect was reduced in the presence of cobalt chloride which blocks voltage-dependent calcium channels. In addition, TS-TEC in culture were immunoreactive to antibody AG7. This antibody was raised to a membrane-bound antigen involved in calcium influx subsequent to progesterone binding in sperm. Thus we suggest that progesterone acts upon many aspects of TS-TEC physiology through both cytoplasmic and membrane-bound receptors.
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PMID:Rapid progesterone actions on thymulin-secreting epithelial cells cultured from rat thymus. 987 32

Cholecystokinin (CCK) dose-dependently stimulates enzyme secretion or loss of cell integrity in the exocrine pancreas. Signaling mechanims include tyrosine phosphorylation of p125(FAK) and paxillin. Here, we examine their potential function. Maximum phosphorylation of both proteins was observed after stimulation of freshly isolated rat pancreatic acini with 10 nM CCK, a concentration known to initiate breakdown of the terminal actin web and cell damage. Under these conditions, CCK initiated transient redistribution of paxillin from the apical cytosol to the apical and lateral plasma membrane within 2 min, where it colocalized with the terminal actin web. Relocation of paxillin was confirmed in subcellular fractions by western blotting and coincided with maximum phosphorylation of membrane-bound p125(FAK) and paxillin. Subsequently, paxillin was redistributed to the basolateral cytosol and was degraded. p125(FAK) remained membrane-bound. We conclude that phosphorylation and redistribution of paxillin and phosphorylation of p125(FAK) may participate in the CCK-induced disassembly of acinar cell actin.
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PMID:Cholecystokinin-induced redistribution of paxillin in rat pancreatic acinar cells. 991 50

The E-cadherin-catenin complex is pivotal for the regulation of cancer invasion. It not only serves cell-cell adhesion but also transduces signals from the micro-environment to other molecular complexes possibly implicated in invasion. Both functions are disturbed when the extracellular part of E-cadherin is cleaved off. Moreover, upon release into the environment, the E-cadherin fragments may interfere with intact complexes, as indicated by experiments with His-Ala-Val (HAV)-containing peptides that are homologous to parts of the first extracellular domain of E-cadherin. Scatter factor/hepatocyte growth factor (SF/HGF), on binding to its c-met tyrosine kinase receptor, can induce invasion through tyrosine phosphorylation of beta-catenin. SF/HGF-induced invasion is also associated with phosphorylation of pp125FAK, and both invasion and phosphorylation are inhibited by platelet-activating factor (PAF). Activation of the membrane-bound non-receptor tyrosine kinase pp60src can also induce invasion. Signal transduction pathways starting from pp60src include E-cadherin-associated beta-catenin as well as the focal adhesion kinase pp125FAK. Whereas all invasion-inducing pathways implicate phosphoinositide 3-kinase, the PAF pathway seems to be E-cadherin-catenin-independent. We conclude that cancer cell invasion is regulated by paracrine and autocrine factors that are released upon cross-talk with the host cells.
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PMID:Extracellular regulation of cancer invasion: the E-cadherin-catenin and other pathways. 1032 Sep 32


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