Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are 'cancer-specific', which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase platelet-derived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.
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PMID:Novel anticancer drug discovery. 1041 54

It is now well-established that phospholipase D is transiently stimulated upon activation by G-protein-coupled and receptor tyrosine kinase cell surface receptors in mammalian cells. Over the last 5 years, a tremendous effort has gone to identify the major intracellular regulators of mammalian phospholipase D and to the cloning of two mammalian phospholipase D enzymes (phospholipase D1 and D2). In this chapter, we review the physiological function of mammalian phospholipase D1 that is synergistically stimulated by ADP ribosylation factor, Rho and protein kinase Calpha. We discuss the function of this enzyme in membrane traffic, emphasising the possible integrated relationships between consumption of vesicles in regulated exocytosis, membrane delivery and constitutive membrane traffic.
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PMID:Phospholipase D and membrane traffic. Potential roles in regulated exocytosis, membrane delivery and vesicle budding. 1042 98

We have previously shown that endothelin-1 (ET-1) modulates mechanical stretch-induced hypertrophic responses such as extracellular signal-regulated protein kinase (ERK) activation in cardiac myocytes. This study was undertaken to elucidate the ET-1-evoked signal transduction pathways leading to ERK activation. ET-1 was added to cultured cardiac myocytes of neonatal rats with or without a variety of inhibitors. ET-1 activated ERKs, which were followed by an increase in protein synthesis, and inhibition of protein kinase C activities by calphostin C completely suppressed the ET-1-induced ERK activation. We next examined whether tyrosine kinases or Ras are involved in ET-1-induced signaling pathways in cardiomyocytes. Pretreatment with a receptor tyrosine kinase inhibitor did not attenuate ET-1-induced activation of ERKs. Also, co-transfection of the dominant-negative mutant of Ras or active mutant of C-terminal Src kinase, a tyrosine kinase which inhibits Src family tyrosine kinases, with hemagglutinin-tagged ERK2 had no effects on ET-1-induced ERK2 activation. On the other hand, blockade of Raf-1 kinase function by overexpression of the dominant-negative mutant of Raf-1 kinase completely inhibited ET-1-induced ERK2 activation. These results suggest that protein kinase C and Raf-1 kinase, but not Src or Ras, are critical to ET-1-induced ERK activation in cardiac myocytes.
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PMID:Hypertrophic responses of cardiomyocytes induced by endothelin-1 through the protein kinase C-dependent but Src and Ras-independent pathways. 1048 27

Our previous study demonstrated increases in epidermal growth factor receptor (EGF-R) phosphorylation and receptor tyrosine kinase and extracellular signal-regulated kinase (ERK1 and ERK2) activities in the ulcer margin of experimental gastric ulcer during healing. However, the intermediate steps linking activated receptor tyrosine kinase to ERKs during ulcer healing are as yet unknown. Raf-1 is upstream of mitogen-activated protein kinases (MAPK/ERK) and can be activated by Ras-dependent and/or Ras-independent mechanisms. Therefore, we studied Raf-1 activity, its potential activators protein kinase C (PKC) and Ras, and expression and associations of adapter proteins Shc, Grb2, and Sos during experimental gastric ulcer healing. To investigate if Raf-1-ERK activation is attributable to the epithelial component of ulcer margins, we studied the effect of EGF on PKC, Ras, and ERK activities in a rat gastric epithelial cell line (RGM1). Our results demonstrate that gastric ulceration significantly increases Raf-1 kinase activity, Grb2 and Ras protein, and Shc-Grb2 and Grb2-Sos complex levels. In contrast, PKC activity and protein level were significantly decreased in the ulcer margins. In RGM1 cells, EGF significantly increased Ras and ERK2 activities without affecting PKC activity. These findings indicate that Raf-1 activation during gastric ulcer healing is Ras mediated, involves Shc-Grb2-Sos, and is PKC-independent.
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PMID:Activation of Raf-1 during experimental gastric ulcer healing is Ras-mediated and protein kinase C-independent. 1055 Mar 32

Fusion of tumorigenic HeLa cells with human skin fibroblasts results in chromosomally stable hybrids that are nontumorigenic and no longer express the HeLa tumor-associated marker intestinal alkaline phosphatase (IAP). Previous studies of spontaneous tumorigenic segregants from the nontumorigenic hybrids implicated the loss of one copy of human fibroblast chromosome 11 in the concomitant reexpression of tumorigenicity. In an attempt to identify genes involved in the control of tumorigenic expression, we performed differential display screening of nontumorigenic hybrid cells and tumorigenic segregants. Subsequent northern blot analyses reproducibly showed 17 differentially expressed genes, eight of which were expressed differentially in the nontumorigenic hybrids and nine of which were expressed differentially in the tumorigenic hybrids. The former were genes for 80K-L protein (a substrate of protein kinase C), AXL/UFO (a receptor tyrosine kinase), insulin-like growth factor binding protein 3, apolipoprotein AI regulatory protein, collagen type I alpha-2 chain, transforming growth factor-beta-induced gene product 3 (BIGH3), pregnancy-specific beta-1-glycoprotein, and fibroblast activation protein alpha. The latter nine genes were genes for serum/glucocorticoid-regulated kinase (SGK; a serine/threonine protein kinase), PTPCAAX1 (a tyrosine phosphatase), CXCR-4 (a G-protein-coupled membrane receptor), L-kynurenine hydrolase, beta-1, 4-galactosyltransferase, keratin 8, keratin 17, and H19 and a novel gene. The differential expression of these genes provided several interesting candidates for regulation of tumorigenic expression, including those involved in signal transduction and the extracellular matrix, cytoskeletal proteins, cell-surface enzyme, and the H19 gene.
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PMID:Differential gene expression in tumorigenic and nontumorigenic HeLa x normal human fibroblast hybrid cells. 1056 6

During the first postnatal week, glial cell production for the neocortex continues in the neocortical subventricular zone. During this time, the proenkephalin gene (PEnk) is expressed in numerous cells of the subventricular zone and of the adjacent neocortex. When neocortical astroglial cells are brought into dissociation culture, they also produce PEnk mRNA. We have investigated the effect of pituitary adenylate cyclase activating peptide-38 (PACAP38) on PEnk gene expression in dissociation cultures as well as in slice cultures, which contained the subventricular zone and the adjacent neocortex. PACAP38 enhanced the levels of PEnk mRNA in both culture systems. In dissociated astroglial cells, inhibition of protein kinase A, of p44,42 mitogen-activated protein kinase as well as of the EGF-receptor tyrosine kinase by H89, PD98059 and AG1478, respectively, reduced the PACAP38-induced expression in a synergistic manner. In the neocortical part of the slice cultures, the effect of PACAP38 on PEnk gene expression was inhibited only by H89 and PD98059. Here, protein kinase A and p44,42 MAP kinases shared a mechanism which increased the gene expression. Surprisingly, the expression of the PEnk gene in the glial progenitors of the subventricular zone as induced by PACAP38 was not affected by any of the three protein kinase inhibitors, but was blocked by the unspecific kinase inhibitor H7. It is concluded that PACAP38 induced the PEnk gene expression in both culture systems in a cell-type specific manner.
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PMID:Evidence for cell specific regulation by PACAP38 of the proenkephalin gene expression in neocortical cells. 1075 74

Receptor tyrosine kinases are regulators of diverse cellular functions including cell growth, cell survival, differentiation, locomotion, and morphogenesis. Activation of the cAMP-dependent protein kinase A inhibits receptor tyrosine kinase-stimulated growth responses in a number of cell types. In this study, we investigated the consequences of elevated cAMP on growth factor-mediated keratinocyte migration and matrix metalloproteinase (MMP)-9 induction in a human keratinocyte cell line. We found that elevation of intracellular cAMP by forskolin abolishes epidermal growth factor (EGF)- or scatter factor/hepatocyte growth factor-dependent colony dispersion. Concentrations of forskolin that inhibit growth factor-induced motility also eliminate EGF- or scatter factor/hepatocyte growth factor-dependent induction of the 92-kDa gelatinase/MMP-9. In contrast to findings obtained in fibroblasts, elevated intracellular cAMP did not interfere with growth factor-dependent activation of the p42/44 extracellular signal-regulated kinases, indicating that cAMP-dependent inhibition of migration and MMP-9 induction does not occur through perturbation of the extracellular signal-regulated kinases/mitogen-activated protein kinase pathway. However, forskolin effectively inhibited EGF-dependent activation of c-Jun N-terminal kinase and p38, demonstrating that cAMP selectively interferes with a different subset of growth factor-induced mitogen-activated protein kinase signaling cascades than reported previously in fibroblasts. These findings illustrate that EGF concurrently activates multiple mitogen-activated protein kinase signaling cascades in keratinocytes and suggests that each pathway contributes to maximal EGF-dependent migration and proteinase induction.
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PMID:Elevation of intracellular cAMP inhibits growth factor-mediated matrix metalloproteinase-9 induction and keratinocyte migration. 1086 Sep 36

Muscle glucose uptake, glycogen synthase activity, and insulin signaling were investigated in response to a physiological hyperinsulinemic (600 pmol/l)-euglycemic clamp in young healthy subjects. Four hours before the clamp, the subjects performed one-legged exercise for 1 h. In the exercised leg, insulin more rapidly activated glucose uptake (half activation time [t1/2] = 11 vs. 34 min) and glycogen synthase activity (t1/2 = 8 vs. 17 min), and the magnitude of increase was two- to fourfold higher compared with the rested leg. However, prior exercise did not result in a greater or more rapid increase in insulin-induced receptor tyrosine kinase (IRTK) activity (t1/2 = 50 min), serine phosphorylation of Akt (t1/2 = 1-2 min), or serine phosphorylation of glycogen synthase kinase-3 (GSK-3) (t1/2 = 1-2 min) or in a larger or more rapid decrease in GSK-3 activity (t1/2 = 3-8 min). Thirty minutes after cessation of insulin infusion, glucose uptake, glycogen synthase activity, and signaling events were partially reversed in both the rested and the exercised leg. We conclude the following: 1) physiological hyperinsulinemia induces sustained activation of insulin-signaling molecules in human skeletal muscle; 2) the more distal insulin-signaling components (Akt, GSK-3) are activated much more rapidly than the proximal signaling molecules (IRTK as well as insulin receptor substrate 1 and phosphatidylinositol 3-kinase [Wojtaszewski et al., Diabetes 46:1775-1781, 1997]); and 3) prior exercise increases insulin stimulation of both glucose uptake and glycogen synthase activity in the absence of an upregulation of signaling events in human skeletal muscle.
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PMID:Insulin signaling and insulin sensitivity after exercise in human skeletal muscle. 1086 52

The HER-2/erbB-2/c-neu proto-oncogene encodes for an EGF receptor-like protein which has been implicated in the pathogenesis of several human malignancies. Although much has been learned about the physiological significance of this receptor tyrosine kinase, its catalytic mechanism remains poorly understood. We have expressed, purified, and characterized two recombinant proteins corresponding to a full-length (HCD) and truncated (HKD) construct of the HER-2 intracellular tyrosine kinase domain and have identified an optimal substrate (GGMEDIYFEFMGGKKK; HER2Peptide) through screening of a degenerate peptide library. We have conducted a transient kinetic analysis of the HER-2 proteins (HCD and HKD) to illuminate mechanistic details of the HER-2 pathway. In particular, stopped-flow fluorescence studies with mant (N-methylanthraniloyl)-nucleotide derivatives provided direct measurements of the association and dissociation rate constants for these nucleotide interactions with the HER-2 recombinant proteins, thereby enabling the determination of nucleotide K(d) values. Moreover, the actual step of chemical catalysis was isolated using rapid chemical quench techniques and shown to occur approximately 3-fold faster than the steady-state rate which corresponds to product release. Evidence is also provided that suggests a conformational change that is partially rate-limiting at least in HCD. Furthermore, the role that the phosphorylation state of the protein may play on catalysis was examined. Studies carried out with pre-phosphorylated recombinant HER-2 proteins suggest that while autophosphorylation is not a prerequisite for enzymatic activity, this protein modification actually directly affects the catalytic mechanism by enhancing the rate of ADP release and that of the rate-limiting step. While a pre-steady-state kinetic analysis has been carried out on the catalytic subunit of cAMP-dependent serine/threonine kinase, to our knowledge, this study represents the first reported transient kinetic investigation of a receptor tyrosine kinase. This work serves as a basis for comparison of these two important protein kinase families and in this report we highlight these similarities and differences.
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PMID:Insights into the HER-2 receptor tyrosine kinase mechanism and substrate specificity using a transient kinetic analysis. 1093 96

Glial cell line derived neurotrophic factor (GDNF) signals through a multicomponent receptor complex consisting of RET receptor tyrosine kinase and a member of GDNF family receptor alpha (GFRalpha). Recently, it was shown that tyrosine 1062 in RET represents a binding site for SHC adaptor proteins and is crucial for both RAS/mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from tyrosine 1062, using human neuroblastoma and primitive neuroectodermal tumor cell lines expressing RET at high levels. In response to GDNF stimulation, SHC bound to GAB1 and GRB2 adaptor proteins as well as RET, and SHC and GAB1 were highly phosphorylated on tyrosine. The complex formation consisting of SHC, GAB1 and GRB2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine. Tyrosine-phosphorylated GAB1 was also associated with p85 subunit of PI3-K, resulting in PI3-K and AKT activation, whereas SHC-GRB2-SOS complex was responsible for the RAS/ERK signaling pathway. These results suggested that the RAS and PI3-K pathways activated by GDNF bifurcate mainly through SHC bound to tyrosine 1062 in RET. Furthermore, using luciferase reporter-gene assays, we found that the RAS/ERK and PI3-K signaling pathways are important for activation of CREB and NF-kappaB in GDNF-treated cells, respectively. Oncogene (2000) 19, 4469 - 4475.
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PMID:Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. 1100 19


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