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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sequential protein kinase reactions involve the phosphorylation and activation of multiple kinases in a pathway. The growth factor receptor tyrosine kinase regulation of the mitogen-activated protein kinase (MAPK) pathway was defined in 1993. The MAPK pathway involves sequential protein kinase reactions. Notable advances were made in defining tyrosine kinase receptor regulation of Ras, and these discoveries were combined with the identification of Raf-1, a serine-threonine protein kinase in the MAPK pathway, as an effector for Ras GTP.
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PMID:Sequential protein kinase reactions controlling cell growth and differentiation. 802 15

The Met proto-oncogene product is a tyrosine kinase receptor whose ligand is hepatocyte growth factor (HGF). The Met protein is first synthesized in the hepatocytes as a single chain precursor, or p170MET proreceptor, and is then processed to a mature heterodimer receptor consisting of an extracellular alpha subunit (p50 alpha MET) and a transmembrane beta subunit (p 145 beta MET). The beta subunit has a protein kinase domain which is activated through phosphorylation on tyrosine residue by the binding of HGF to the receptor. In order to elucidate the function of the Met gene product in hepatic disorders, we analyzed the expression and tyrosine phosphorylation of the Met protein on regeneration and carcinogenesis of the liver. For studies on carcinogenesis we used human hepatoma tissues, and for studies on regeneration we used rat hepatectomy. Two antibodies were used for western blotting; a mouse monoclonal anti-phosphotyrosine antibody, which recognizes phosphorylated tyrosine residue in proteins, and a polyclonal rabbit anti-Met antibody, which recognizes the C-terminus of both the Met beta chains and proreceptor. To compare the amount of protein in each experiment, the results of western blotting were evaluated using an image analyzing system. In experiments involving rats with partial hepatectomy, a decreased expression of the proreceptor with a decreased amount of tyrosine phosphorylation was observed within 12 hours of hepatectomy. However, there were no significant changes of the Met beta subunit during the experiment. These data suggest that the Met proreceptor is decreased in the early stages of liver regeneration. In experiments on human samples surgically removed from 18 patients with hepatocellular carcinoma, the met proteins, p 145 beta MET and p 160 MET proreceptor, were expressed both in cancer tissues (12/18, and 10/18, respectively) and in non-cancer tissues (8/18, and 15/18, respectively). From the comparative analyses of the intensity of the signals in cancerous region against those of non-cancerous region in the 18 individual cases, it was demonstrated that expression of p 160 MET proreceptor was increased in non-cancerous region more significantly than in cancerous region (p < 0.05). On the contrary, expression of p145 beta MET was increased in cancerous region more significantly than in non-cancerous region (p < 0.05), except for a few cases of poorly differentiated carcinomas in which p 145 beta MET signal was not detected. These findings suggested that a processing pathway from the proreceptor to the mature Met receptor is amplified in carcinogenesis of the liver.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Analysis of the hepatocyte growth factor receptor in regeneration and oncogenesis of hepatocytes]. 815 55

The amphibian tetradecapeptide bombesin as well as the bombesin-related mammalian peptides are potent mitogens for Swiss 3T3 cells. Other sole mitogens for Swiss 3T3 cells, such as PDGF and FGF, invariably signal through a tyrosine kinase receptor. The bombesin receptor has been cloned from Swiss 3T3 fibroblasts and was shown to be a member of the family of G-protein-linked neuropeptide receptors, whose sequence does not reveal a protein kinase domain. Upon binding to its receptor, bombesin evokes a complex cascade of early biochemical events including inositol 1,4,5-trisphosphate-induced mobilization of intracellular Ca2+, Na+ and K+ fluxes, PK-C activation, transmodulation of the EGF-receptor, accumulation and expression of the proto-oncogenes c-fos and c-myc and cAMP production. The intermediates in this signaling pathway are still largely unknown. Since many hormones and neuropeptides that signal through similar receptors with seven membrane spanning domains are by themselves not mitogenic for Swiss 3T3 fibroblasts, we suggest that bombesin acts through a rather special signaling pathway. Although its receptor does not feature a cytoplasmic tyrosine kinase domain, bombesin rapidly stimulates the tyrosine phosphorylation of multiple protein substrates, which are however quite distinct from the usual targets of tyrosine kinase receptors. Yet, a similar cascade of Ser/Thr protein kinases is activated downstream of these differentiating tyrosine kinase events, since, like EGF or insulin, bombesin rapidly stimulates the activity of two MBP kinases as well as several S6 peptide kinases. The present report furthermore implicates CK-2 in the early signal transduction pathway of this mitogen, and it is postulated that the activation of CK-2 may be an intrinsic property of "sole mitogens" like bombesin, as it may be a compulsory event leading to cell division. In that respect, CK-2 may also be the point of integration of multiple signaling pathways, initiated by several different growth factors which by their synergistic actions make cell proliferation possible.
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PMID:Early responses in mitogenic signaling, bombesin induced protein phosphorylations in Swiss 3T3 cells. 839 34

Human parotid tumors were evaluated for the activation of the phosphotyrosine signaling pathway by Western blot, enzyme activity assay, and reverse transcriptase-polymerase chain reaction. Warthin's tumor and mucoepidermoid carcinomas had the greatest level of tyrosine phosphorylated proteins identified in plasma membrane fractions. These tumors, along with pleomorphic adenocarcinoma, showed high levels of membrane expression of the tyrosine kinase receptor, c-erbB-2, and phosphatidylinositol-3-kinase. Expression of the epidermal growth factor receptor was confined to normal tissue. The level of mRNA for c-erb was elevated only in mucoepidermoid carcinomas. Messenger RNA levels for ras were unchanged from control levels in all tumors, while the level of src mRNA was higher in the tumor samples than the normal parotid tissue. The activities of several signal transduction kinases, including protein kinase A and C were elevated in tumor tissue (7.7- to 18.9- and 0.4- to 3.7-fold higher, respectively), relative to surrounding normal tissue. While the level of glandular amylase was reduced (22%-0% of normal levels) in the tumor tissue, epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) content was dramatically higher in the neoplastic tissue (10- to 170-fold and 4.6- to 6.0-fold, respectively). These results suggest that with the presence of elevated levels of EGF, TGFalpha, and the oncoprotein receptor c-erbB-2 in the membrane of parotid tumors, cell proliferation and activation of the phosphotyrosine signal transduction pathway may involve autocrine stimulation through the expression of high levels of growth factor and receptor in the same tissue.
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PMID:Alterations in the level of phosphotyrosine signal transduction constituents in human parotid tumors. 863 6

Protein kinase C (PKC) is a family of serine/threonine protein kinase isoforms that is important to intracellular enzymes for both tyrosine kinase receptors and G protein coupled receptors. However, which isoforms are linked to which class of receptors in endothelial cell signaling is not known. Moreover, the PKC isoforms in endothelial cells have not been thoroughly characterized. We tested the hypothesis that specific PKC isoforms are involved in different signaling pathways. PKC isoform expression was assessed by using reverse transcription polymerase chain reaction and Western blotting. The spatial distribution of PKC after stimulation of the cells with basic fibroblast growth factor (bFGF) and thrombin was examined by using confocal microscopy. Expression of PKC alpha, delta, epsilon, theta, and zeta was detectable on both the mRNA and protein levels. In resting cells, PKC alpha and epsilon were mostly distributed in the cytosol, while PKC alpha and epsilon were also present in the nucleus. Nuclear immunoreactivity of PKC alpha and epsilon increased significantly between passages 1 and 3. The phorbol ester TPA induced a rearrangement of PKC delta and a translocation of PKC alpha and epsilon to the nucleus. Treatment of endothelial cells with TPA for 24 hours caused PKC alpha, delta, and epsilon to disappear, while PKC zeta was not influenced by TPA. bFGF induced a rapid assembly of PKC alpha along cytosolic structures, followed by a translocation of the isoform toward the perinuclear region and into the nucleus. bFGF had a smaller effect on PKC epsilon. In contrast, thrombin had a similar effect on nuclear translocation of PKC alpha, did not influence PKC epsilon, and induced a rapid nuclear translocation of PKC zeta. Thus, tyrosine kinase receptor activation via bFGF induced a rapid association of PKC alpha and epsilon with nuclear structures, while activation of the G protein-coupled thrombin receptor increased mostly nuclear PKC zeta. The translocation of PKC isoforms into the nucleus by growth-promoting factors may be important for the induction of endothelial cell growth.
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PMID:Endothelial cell tyrosine kinase receptor and G protein-coupled receptor activation involves distinct protein kinase C isoforms. 896 26

The binding of the spermatozoon to the oocyte zona pellucida (ZP) occurs via specific receptors localized over the anterior head region of the spermatozoon. Zona pellucida binding stimulates the spermatozoa to undergo the acrosome reaction resulting in the release of hydrolytic enzymes and in the exposure of new membrane domains, both of which are essential for fertilization. We suggest that ZP binds to at least two different receptors in the plasma membrane. One (R) is a Gi-coupled receptor that activates phospholipase C (PLC) beta 1. The other (TK) is a tyrosine kinase receptor coupled to PLC gamma. Binding to R would regulate adenylyl cyclase (AC) leading to elevation of cAMP and protein kinase (PKA) activation. The PKA activates a voltage-dependent Ca2+ channel in the outer acrosomal membrane which releases Ca2+ from the interior of the acrosome to the cytosol. This is the first, relatively small, rise in [Ca2+]i (I) which leads to activation of the PLC gamma. The products of phosphatidyl-inositol bisphosphate (PIP2) hydrolysis by PLC diacylglycerol (DAG) and inositol-trisphosphate (IP3) will lead to PKC translocation to the plasma membrane and its activation. PKC opens a voltage-dependent Ca2+ channel (L) in the plasma membrane, leading to the second (II) higher increase in [Ca2+]i. The Gi or TK can also activate an Na+/H+ exchanger leading to alkalization of the cytosol. PKC also activates phospholipase A2 (PLA2) to generate arachidonic acid (AA) from membrane phospholipids. AA will be converted to prostaglandins (PG) and leukotriens (LT) by the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) respectively. The increase in [Ca2+]i and pH leads to membrane fusion and acrosomal exocytosis.
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PMID:The biochemistry of the acrosome reaction. 923 45

The stimulation of glucose transport is one of the early cellular responses to growth factors and is essential for cell proliferation, yet the molecular processes that underlie this response are poorly defined. The aim of this study was to characterize the role of the low-molecular-mass G-proteins, Ras and Rho, and their downstream targets, Raf protein kinase and phosphatidylinositol 3-kinase, in the regulation of glucose transport in Xenopus oocytes by two distinct growth-factor receptors: the insulin-like growth factor I (IGF-I) tyrosine kinase receptor and the heterotrimeric G-protein-coupled lysophosphatidic acid (LPA) receptor. Microinjection of a neutralizing anti-Ras antibody partially blocked IGF-I-stimulated deoxyglucose uptake but was without effect on LPA-stimulated deoxyglucose uptake. In contrast, microinjection of the C3 coenzyme of botulinum toxin, which selectively ADP-ribosylates and inactivates Rho, inhibited LPA-stimulated, but not IGF-I-stimulated, deoxyglucose uptake. Similarly, LPA- but not IGF-I-stimulated deoxyglucose uptake was attenuated in oocytes expressing a dominant negative rho construct. Cells expressing a dominant negative mutant of Raf protein kinase exhibited markedly reduced sensitivity to both LPA and IGF-I, consistent with a role for endogenous Raf in glucose uptake by both growth factors. Furthermore, expression of a constitutively activated form of raf-1 resulted in a growth-factor-independent increase in deoxyglucose uptake. Measurements of phosphatidylinositol 3-kinase activity in microinjected cells support the hypothesis that the IGF-I receptor stimulates glucose transport by a Ras-dependent activation of phosphatidylinositol 3-kinase, whereas the G-protein-coupled LPA receptor controls this response by a pathway that involves Rho-dependent activation of a distinct phosphatidylinositol 3-kinase. Thus we provide evidence for clear differences in the signalling pathways that control glucose transport by G-protein-coupled and tyrosine kinase growth-factor receptors. Furthermore this is the first demonstration that active Rho is involved in the signalling pathways that regulate glucose uptake in response to some growth factors.
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PMID:Characterization of the intracellular signalling pathways that underlie growth-factor-stimulated glucose transport in Xenopus oocytes: evidence for ras- and rho-dependent pathways of phosphatidylinositol 3-kinase activation. 927 Oct 83

Intracellular signaling events occurring downstream of receptor activation for the colony-stimulating factors GM-CSF and G-CSF and Steel factor the latter a member of the tyrosine kinase receptor family of hematopoietic growth factors, are discussed. Hematopoietic signaling pathways, including the Ras/Raf-1/MAP kinase cascade and the Jak-STAT pathway are defined and links existing between separate signaling pathways are discussed. Emphasis is given to exploring the relationships that exist between activation of receptor-associated proteins and signal transduction pathways, and the regulation of gene transcription, translation, and hematopoietic cell proliferation. A model system exploring the synergistic interaction between GM-CSF and Steel factor in the regulation of hematopoietic cell proliferation is presented.
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PMID:Advances in understanding the postreceptor mechanisms of action of GM-CSF, G-CSF, and Steel factor. 937 74

Acrosomal exocytosis occurs after the binding of the spermatozoon to the zona pellucida of the oocyte via specific receptors. We suggest that the zona pellucida binds to at least two different receptors in the plasma membrane. One (R) is a Gi-coupled receptor that activates phospholipase C beta 1. The other (TK) is a tyrosine kinase receptor coupled to phospholipase C gamma. Binding to R would regulate adenylyl cyclase leading to an increase in cyclic adenosine monophosphate and protein kinase A activation. The protein kinase A activates a voltage-dependent Ca2+ channel in the outer acrosomal membrane that releases Ca2+ from the interior of the acrosome to the cytosol. This is the first (I), relatively small, rise in intracellular Ca2+ which leads to activation of the phospholipase C gamma. The products of phosphatidyl-inositol bisphosphate hydrolysis by phospholipase C, diacylglycerol and inositol-trisphosphate lead to protein kinase C translocation to the plasma membrane and its activation. Protein kinase C opens a voltage-dependent Ca2+ channel (L) in the plasma membrane, leading to the second (II), higher, increase in intracellular Ca2+ leading to acrosomal exocytosis. Spermine, a physiological constituent of the seminal plasma regulates sperm acrosomal exocytosis by modulating intracellular Ca2+ binding sites and phospholipase C activity. Spermine is rapidly incorporated into the sperm cells during ejaculation and temporarily inhibits premature capacitation and acrosome reaction. During the passage of the spermatozoon through the female genital tract, there is a progressive depletion of spermine from spermatozoa, so that capacitation and consequently the acrosomal exocytosis take place at the appropriate time, when the spermatozoon reaches the vicinity of the egg.
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PMID:Regulatory mechanisms in acrosomal exocytosis. 941 80

The pineal hormone, melatonin, inhibits proliferation of estrogen receptor (ER)-positive MCF-7 human breast cancer cells, modulates both ER mRNA and protein expression, and appears to be serum dependent, indicating interaction between melatonin and serum components. To examine the effects of melatonin on ER activity, ER transactivation assays were performed by transiently transfecting MCF-7 cells with an ERE-luciferase reporter construct. MCF-7 cells pre-treated with melatonin for as little as 5 min followed by either epidermal growth factor (EGF) or insulin resulted in the estrogen-independent transactivation of the ER. None of the compounds when used alone transactivated the ER. The ability of melatonin and EGF to transactivate the ER was abolished by the addition of the antiestrogen, ICI 164384, suggesting that melatonin and EGF co-operate to transactivate the ER. The modulation of ER transactivation was associated with changes in mitogen activated protein kinase activity and ER phosphorylation. This ER transactivation was blocked by pertussis toxin, a Galpha i-protein-coupled receptor inhibitor, suggesting cross talk between the G-protein-coupled melatonin receptor pathway and the EGF/insulin tyrosine kinase receptor pathways in modulating ER transactivation. Exactly how the ability of melatonin in combination with EGF to transactivate the ER relates to melatonin's observed growth suppressive effects is not clear. It is possible that, although melatonin and EGF transactivate the ER, this transactivation does not result in the full transcription of estrogen-responsive genes, but rather, makes the ER refractory to activation by estradiol, thus, blocking the mitogenic actions of estradiol.
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PMID:Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors. 972 86


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