Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that pp60c-src is a substrate for protein kinase C in vivo and that the target of protein kinase C phosphorylation in mammalian pp60c-src is serine 12. We now demonstrate that in addition to tumor promoters, all activators of phosphatidylinositol turnover that we have tested in fibroblasts (platelet-derived growth factor, fibroblast growth factor, serum, vasopressin, sodium orthovanadate, and prostaglandin F2 alpha) lead to the phosphorylation of pp60c-src at serine 12. In addition to stimulating serine 12 phosphorylation in pp60c-src, platelet-derived growth factor treatment of quiescent fibroblasts induces phosphorylation of one or two additional serine residues and one tyrosine residue within the N-terminal 16 kilodaltons of the enzyme and activates its immune complex protein-tyrosine kinase activity.
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PMID:Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity. 246 76

Upon activation platelets show elevated protein tyrosine phosphorylation, and translocation of the protein tyrosine kinase pp60c-src from the plasma membrane to the cytoskeleton occurs. We therefore investigated whether tyrosine phosphorylation also increases in the cytoskeletal compartment. Here we show that almost identical patterns of phosphotyrosine-containing proteins are detectable in the cytoskeleton after platelet stimulation with compounds that directly (phorbol 12-myristate, 13-acetate) or indirectly (thrombin, vasopressin, collagen, ADP) activate protein kinase C. The apparent molecular masses of the proteins phosphorylated at tyrosine residues are 145, 130, 100, 85, 80, 60, 56, 54 and 38 kDa. Elevation of cyclic AMP by prostaglandin E1 had no effect. Concentrations of thrombin as low as 0.01 units per ml are able to cause tyrosine phosphorylation of multiple proteins. The time course of protein tyrosine phosphorylation for thrombin- and vasopressin-stimulated platelets revealed a rapid increase in the cytoskeleton within 5 to 20 s following activation consistent with a role in early events of platelet function.
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PMID:Rapid protein tyrosine phosphorylation in the cytoskeleton of stimulated human platelets. 753 10

Human blood platelets contain high levels of non-receptor protein tyrosine kinases of the Src family, particularly pp60c-src, suggesting an important role for these enzymes in platelet physiology. Indeed, in response to various agonists of platelet function, a number of proteins become phosphorylated at tyrosine residues. However, no enzymic activation of an Src-related tyrosine kinase has yet been shown in platelets. In searching for the kinase(s) responsible, we found that all agonists tested that directly or indirectly activate protein kinase C in platelets (phorbol 12-myristate, 13-acetate, thrombin, vasopressin, collagen, calcium ionophore A23187) increased the overall activity of pp60c-src determined by IgG phosphorylation in an immunocomplex assay in the presence of low ATP concentrations. On the other hand, elevation of cyclic AMP directly by forskolin or indirectly by prostaglandin E1, or elevation of cyclic GMP by sodium nitroprusside did not significantly affect the activity of the enzyme. To substantiate the differences in enzyme activity, we determined Km and Vmax, values of pp60c-src from resting and thrombin-stimulated platelets. Thrombin treatment increased substrate affinity of pp60c-src as indicated by a 2- to 3-fold decrease in the Km values for ATP and the exogenous protein substrate casein. Vmax. values were only slightly altered under the assay conditions used. To further rule out modifications of pp60c-src in phosphorylation as a probable cause of the changed substrate affinity, we analysed tryptic phosphopeptides of immunoprecipitated, 32P-labelled pp60c-src of unstimulated and stimulated platelets. The platelet agonists listed above induced an increase in pp60c-src phosphorylation at Ser-12, which is the amino acid phosphorylated by protein kinase C. Surprisingly, we found that elevation of cyclic AMP did not affect 32P labelling of pp60c-src. On the basis of our data, we suggest that phosphorylation at Ser-12 might be one of the signal-triggering events that cause the increase in substrate affinity of pp60c-src.
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PMID:Substrate affinity of the protein tyrosine kinase pp60c-src is increased on thrombin stimulation of human platelets. 769 43

G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) activate numerous cellular signals through the combined actions of G proteins, GPCR kinases, and arrestins. Although arrestins have traditionally been thought of as mediating GPCR desensitization, they have now been shown to play important roles in the internalization, trafficking, and signaling of many GPCRs. We demonstrate that in cells devoid of arrestins, the stimulation of numerous GPCRs including the N-formyl peptide receptor (FPR) initiates rapid cell rounding, annexin V positivity, and caspase activation followed by cell death. The apoptotic response is initiated by G protein signaling and involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinases, and c-Src resulting in cytochrome c release from mitochondria and ultimately caspase 9 and caspase 3 activation. Reconstitution with either arrestin-2 or arrestin-3 is completely sufficient to prevent FPR-mediated apoptosis. Surprisingly, a non-desensitizing and non-internalizing mutant of the FPR is unable to initiate apoptosis, indicating that receptor phosphorylation and internalization, but not solely chronic activation due to a lack of desensitization, are critical determinants for the induction of apoptosis by the FPR. We further demonstrate that this response is not unique to the FPR with numerous additional GPCRs, including the V2 vasopressin, angiotensin II (type 1A), and CXCR2 receptors, capable of initiating apoptosis upon stimulation, whereas GPCRs such as the beta(2)-adrenergic receptor and CXCR4 are not capable of initiating apoptotic signaling. These data demonstrate for the first time that arrestins play a critical and completely unexpected role in the suppression GPCR-mediated apoptosis, which we show is a common consequence of GPCR-mediated cellular activation in the absence of arrestins.
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PMID:Arrestins block G protein-coupled receptor-mediated apoptosis. 1505 14

JAK (Janus-activated kinase)-STAT (signal transducers and activators of transcription) signaling is a major signal transduction pathway in mammalian cells. Different growth factors and cytokines were reported as activators of the JAK-STAT pathway in various cell types. Interestingly, arginine-vasopressin (AVP) was never reported as an inducer of the JAK-STAT pathway. In the present study, we show for the first time that AVP stimulation of vascular smooth muscle cells (VSMCs) induces STAT3 tyrosine and serine phosphorylation, followed by nuclear translocation of the phosphorylated STAT3. In addition, we found that AVP induced JAK2 tyrosine phosphorylation. Taken together, these results demonstrate that AVP activates the JAK-STAT pathway in VSMCs. Furthermore, our results indicate that AVP-induced STAT3 tyrosine phosphorylation requires both JAK2 and c-Src tyrosine kinases. The present study also implicates that extracellular signal-regulated kinase (ERK1/2), which are serine/threonine kinases, are the mediators of STAT3 serine phosphorylation upon AVP stimulation. We further suggest that AVP-induced STAT3 serine phosphorylation negatively modulates AVP-induced STAT3 tyrosine phosphorylation. Finally, our results implicate a novel role for the JAK-STAT pathway, mediating AVP-induced VSMC hypertrophy.
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PMID:Arginine-vasopressin activates the JAK-STAT pathway in vascular smooth muscle cells. 1656 10

The V2 vasopressin receptor (V2R) activates the mitogen activated protein kinases (MAPK) ERK1/2 through a mechanism involving the scaffolding protein beta arrestin. Here we report that this activating pathway is independent of G alpha s, G alpha i, G alpha q or G betagamma and that the V2R-mediated activation of G alpha s inhibits ERK1/2 activity in a cAMP/PKA-dependent manner. In the HEK293 cells studied, the beta arrestin-promoted activation was found to dominate over the PKA-mediated inhibition of the pathway, leading to a strong vasopressin-stimulated ERK1/2 activation. Despite the strong MAPK activation and in contrast with other GPCR, V2R did not induce any significant increase in DNA synthesis, consistent with the notion that the stable interaction between V2R and beta arrestin prevents signal propagation to the nucleus. Beta arrestin was found to be essential for the ERK1/2 activation, indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues. Based on the use of selective pharmacological inhibitors, dominant negative mutants and siRNA, we conclude that the beta arrestin-dependent activation of ERK1/2 by the V2R involves c-Src and a metalloproteinase-dependent trans-activation event. These findings demonstrate that beta arrestin is a genuine signalling initiator that can, on its own, engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand.
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PMID:The V2 vasopressin receptor stimulates ERK1/2 activity independently of heterotrimeric G protein signalling. 1685 42

Activation of V(1a) receptor triggers the expression of growth-related immediate-early genes (IEGs), including c-Fos and Egr-1. We found that pre-treatment of rat vascular smooth muscle A-10 cell line with the EGF receptor inhibitor AG1478 or the over-expression of an EGFR dominant negative mutant (HEBCD533) blocked the vasopressin-induced expression of IEGs, suggesting that activation of these early genes mediated by V(1a) receptor is via transactivation of the EGF receptor. Importantly, the inhibition of the metalloproteinases, which catalyzed the shedding of the EGF receptor agonist HB-EGF, selectively blocked the vasopressin-induced expression c-Fos. On the other hand, the inhibition of c-Src selectively blocked the vasopressin-induced expression of Egr-1. Interestingly, in contrast to the expression of c-Fos, the expression of Egr-1 was mediated via the Ras/MEK/MAPK-dependent signalling pathway. Vasopressin-triggered expression of both genes required the release of intracellular calcium, activation of PKC and beta-arrestin 2. These findings demonstrated that vasopressin up-regulated the expression of c-Fos and Erg-1 via transactivation of two distinct EGF receptor-dependent signalling pathways.
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PMID:Vasopressin up-regulates the expression of growth-related immediate-early genes via two distinct EGF receptor transactivation pathways. 1857 97

Clathrin-mediated endocytosis is a complex process regulated at many different levels. We showed previously that activation of the angiotensin type 1 receptor (AT1R), which belongs to the G protein-coupled receptor (GPCR) family, leads to c-Src-dependent tyrosine phosphorylation of beta2-adaptin, a subunit of the clathrin adaptor AP-2. The phosphorylation of beta2-adaptin on tyrosine residue 737 (Y737) negatively regulates its interaction with betaarrestin, another important clathrin adaptor for GPCR internalization. Here we sought to determine whether AP-2 phosphorylation represents a general mechanism for different receptors internalizing through the clathrin pathway. Using a specifically designed antibody against the phosphorylated form of Y737 on beta2-adaptin, we demonstrate that this residue is phosphorylated by AT1R in different cell types like HEK293, COS-7 and vascular smooth muscle cells. Using RNA interference approaches, we reveal that this agonist-mediated event is both betaarrestin- and c-Src-dependent, and that it occurs at the plasma membrane in clathrin-coated vesicles (CCVs). We further show that this is not only a common event employed by other GPCRs like the beta2-adrenergic, vasopressin V2, bradykinin type 2, platelet-activating factor and endothelin A receptors but that the epidermal growth factor receptor is capable of eliciting the phosphorylation of AP-2 in CCVs. Our results imply that tyrosine phosphorylation of Y737 on beta2-adaptin is a common regulatory mechanism employed by different receptors undergoing clathrin-dependent endocytosis, and suggest a wider function for this event than originally anticipated.
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PMID:c-Src-mediated phosphorylation of AP-2 reveals a general mechanism for receptors internalizing through the clathrin pathway. 1893 40

We found that the inhibitor of Rho-kinase fasudil selectively inhibited constriction of isolated rings of the aorta and mesenteric artery in rats in response to application of the agonists of 5HT2A-(DOI and TBC-2) and 5HT1A-receptors (8-OH-DPAT) and did not influence vasoconstriction induced by serotonin. We demonstrate for the first time that application of the agonists of 5HT2C-receptors (MK 212 and SCH 23390) did not influence the tone of "intact" vessels. The marked vasoconstrictory effect of the agonists of 5HT2C-receptors was observed in the vessels preconstricted due to angiotensin II or vasopressin. We found that the inhibitor of Rho-kinase did not influence negatively on MK 212 or SCH 23390-induced constriction of isolated rings of the aorta and mesenteric artery in rats. We suppose.that, in the presence of fasudil, serotonin induces constriction of vessels through the interaction with 5HT2C-receptors and signal transduction from these receptors does not involve Rho-kinase activity. We found that fasudil attenuated vasoconstriction induced by norepinephrine and vasopressin by 40%. We.demonstrated that tyrosine c-Src-kinase plays the most important role in signal transduction from 5HT-receptors because its effects are specific with relation to these receptors.
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PMID:[The Effects of Inhibitors of Rho- and tyrosine c-Src-kinases on serotonin-induced constrictions of the aorta and mesenteric artery in rats]. 2572 Feb 89

We investigated the role of 5HT2C receptors in regulation of blood vessel contractility. We determined expression of 5HT2C receptors in smooth muscle cell line A7r5 as well as on isolated rat aorta. It was shown that strong vasoconstriction effect of 5HT2C receptor agonists - SCH 23390 and MK 212 appeared on blood vessels after preliminary activation of angiotensin ATIA- and vasopressin V1A-receptors. Biphasic contraction (a rhythmic alternation of contraction and subsequent relaxation phases of aoitic rings) and tonic contraction were observed in 75% and 25% of the cases after 5HT2C receptor activation, respectively. Periodic high amplitude constrictions of isolated rat aorta, induced by SCH 23390 and MK 212 agonists, were persisted for a long time (>1 hour). It was revealed that calmodulin and c-Src kinase play a central role in the mechanisms of signal transduction from 5HT2C receptors. Trifluoperazine and PP2, the inhibitors of calmodulin and c-Src kinase, respectively, abolished vasoconstriction reaction of isolated aortic rings in response to SCH 23390 and MK 212 but did not affect the strength gain of the vasoconstriction caused by fluoroaluminate, a G-protein activator. Taken together, these date suggest that 5HT2C receptors are in a latent state in blood vessels (<<silent>> receptors) and activation of these receptors is dependent on the functional state of the receptors of other endogenous vasoconstrictors.
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PMID:[Agonists of 5HT2C-receptors SCH 23390 and MK 212 incresase the force of rat aorta contraction in the presence of vasopressin and angiotensin II]. 2598 Feb 23


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