Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arrestins play an important role in regulating the function of G protein-coupled receptors including receptor desensitization, internalization, down-regulation, and signaling via nonreceptor tyrosine kinases and mitogen-activated protein kinases. Previous studies have revealed that arrestins themselves are also subject to regulation. In the present study, we focused on identifying potential mechanisms involved in regulating the function of arrestin-3. Using metabolic labeling, phosphoamino acid analysis, and mutagenesis studies, we found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. Functional analysis reveals that mutants mimicking the phosphorylated (T382E) and dephosphorylated (T382A or T382V) states of arrestin-3 promote beta(2)-adrenergic receptor internalization and bind clathrin, beta-adaptin, and Src to comparable levels as wild type arrestin-3. This suggests that the phosphorylation of arrestin-3 does not directly regulate interaction with endocytic (clathrin, beta-adaptin) or signaling (Src) components and is in contrast to arrestin-2, where phosphorylation appears to regulate interaction with clathrin and Src. However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex. Differences between the regulatory roles of arrestin-2 and -3 phosphorylation may contribute to the different cellular functions of these proteins in G protein-coupled receptor signaling and regulation.
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PMID:Regulation of arrestin-3 phosphorylation by casein kinase II. 1187 51

Cardiovascular regulation is tightly controlled by signaling through G protein-coupled receptors (GPCRs). beta-Adrenergic receptors (ARs) are GPCRs that regulate inotropy and chronotropy in the heart and mediate vasodilation, which critically influences systemic vascular resistance. GPCR kinases (GRKs), including GRK2 (or betaARK1), phosphorylate and desensitize agonist-activated betaARs. Myocardial GRK2 levels are increased in heart failure and data suggest that vascular levels may also be elevated in hypertension. Therefore, we generated transgenic mice with vascular smooth muscle (VSM) targeted overexpression of GRK2, using a portion of the SM22alpha promoter, to determine its impact on vascular betaAR regulation. VSM betaAR signaling, as determined by adenylyl cyclase and mitogen-activated protein (MAP) kinase activation assays, was attenuated when GRK2 was overexpressed 2- to 3-fold. In vivo vasodilation in response to betaAR stimulation using isoproterenol was attenuated and conscious resting mean arterial blood pressure was elevated from 96 +/- 2 mm Hg in nontransgenic littermate control (NLC) mice (n = 9) to 112 +/- 3 mm Hg and 117 +/- 2 mm Hg in two different lines of SM22alpha-GRK2 transgenic mice (n = 7 and n = 5, respectively; p < 0.05). Interestingly, medial VSM thickness was increased 30% from 29.8 +/- 1.6 microm in NLC mice (n = 6) to 39.4 +/- 1.6 microm in SM22alpha-GRK2 mice (n = 7) (p < 0.05) and vascular GRK2 overexpression was sufficient to cause cardiac hypertrophy. These data indicate that we have developed a unique mouse model of hypertension, providing insight into the contribution that vascular betaAR signaling makes toward resting blood pressure and overall cardiovascular regulation. Moreover, they suggest that GRK2 plays an important role in vascular control and may represent a novel therapeutic target for hypertension.
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PMID:Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates beta-adrenergic receptor signaling and increases resting blood pressure. 1190 Dec 13

Activation of G protein-coupled receptors (GPCRs) leads to stimulation of classical G protein signaling pathways. In addition, GPCRs can activate the mitogen-activated protein kinases (MAPKs) such as the extracellular signal-regulated kinases, c-Jun NH(2)-terminal kinases (JNKs), and p38 MAPKs, and thereby influence cell proliferation, cell differentiation and mitogenesis. Cross talk between GPCRs and receptor tyrosine kinases (RTKs) is an incredibly complex process, and the exact signaling molecules involved are largely dependent on the cell type and the type of receptor that is activated. In this review we investigate recent advances that have been made in understanding the mechanisms of cross talk between GPCRs and RTKs, with a focus on GPCR-mediated activation of the Ras/MAPK pathway, GPCR-induced transactivation of RTKs, GPCR-mediated activation of JNK, and p38 MAPK, integration of signals by RhoGTPases, and activation of G protein signaling pathways by RTKs.
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PMID:Integration of signals from receptor tyrosine kinases and g protein-coupled receptors. 1194 78

Ultraviolet (UV) irradiation induces various cellular responses by activating many UV-responsive enzymes including mitogen-activated protein kinases (MAPKs). Various G protein-coupled receptor agonists also activate MAPKs, but it is not known whether or not G proteins also mediate the UV-induced activation of MAPKs. Therefore, this study was undertaken to determine whether the G protein betagamma-subunit (Gbetagamma) mediates the UV-induced activation of p38 and JNK. Gbetagamma overexpression in COS-1 cells amplified the UV-induced activation of p38 but reduced JNK activation. The overexpression of the C-terminal region of beta-adrenergic receptor kinase (betaARKct) decreased the UV-induced activation of p38 but increased JNK activation. Gbeta(1)gamma(2) expression increased MKK3/6 phosphorylation with a concomitant decrease in MKK4 phosphorylation, which contrasts with betaARKct expression. Gbeta(1)gamma(2) or betaARKct expression resulted in corresponding changes in the transcriptional activity of CHOP and c-Jun. Treatment with a p38 inhibitor, SB203580, or the expression of a kinase-inactive p38 increased the UV-induced JNK activation. Expression of the constitutively active MKK6 decreased the UV-induced JNK activation. In summary, although the endogenous Gbetagamma was found to mediate about half of the UV-induced activation of p38, it was found that exogenous Gbetagamma mediates the bi-directional regulation of UV-induced p38 and JNK activation, and that this bi-directional regulation results from the inhibition of JNK activation by the p38 activated via Gbetagamma in the COS-1 cells.
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PMID:Bi-directional regulation of UV-induced activation of p38 kinase and c-Jun N-terminal kinase by G protein beta gamma-subunits. 1197 90

beta-Arrestin-1 mediates agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCRs) and is also essential for GPCR mitogenic signaling. In addition, insulin-like growth factor I receptor (IGF-IR) endocytosis is facilitated by beta-arrestin-1, and internalization is necessary for IGF-I-stimulated mitogen-activated protein (MAP) kinase activation. Here, we report that treatment of cells for 12 h with insulin (100 ng/ml) induces an approximately 50% decrease in cellular beta-arrestin-1 content due to ubiquitination of beta-arrestin-1 and proteosome-mediated degradation. This insulin-induced decrease in beta-arrestin-1 content was blocked by inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with wortmannin and PD98059, respectively. We also found a marked decrease in the association of beta-arrestin-1 with the IGF-IR and a 55% inhibition of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated, beta-arrestin-1-downregulated cells, there was complete inhibition of lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase phosphorylation. This was associated with a decrease in beta-arrestin-1 association with the beta2-AR as well as a decrease in beta-arrestin-1-Src and Src-beta2-AR association. Ectopic expression of wild-type beta-arrestin-1 in insulin-treated cells in which endogenous beta-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. In conclusion, we found the following. (i) Chronic insulin treatment leads to enhanced beta-arrestin-1 degradation. (ii) This downregulation of endogenous beta-arrestin-1 is associated with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling, which can be rescued by ectopic expression of wild-type beta-arrestin-1. (iii) Finally, these results describe a novel mechanism for heterologous desensitization, whereby insulin treatment can impair GPCR signaling, and highlight the importance of beta-arrestin-1 as a target molecule for this desensitization mechanism.
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PMID:Insulin induces heterologous desensitization of G-protein-coupled receptor and insulin-like growth factor I signaling by downregulating beta-arrestin-1. 1216 19

The open reading frame (ORF) 74 of gamma-2-herpesviruses encodes a G protein-coupled receptor which is highly conserved in members of this subfamily and is homologous to the CXCR2 chemokine receptor. The viral G protein-coupled receptor has been implicated in viral pathogenesis. However, the advantage of such chemokine receptor homologues to the virus is currently unknown. To address this, we constructed ORF74 deletion mutants of a mouse gamma-2-herpesvirus (MHV-68) and examined the effect of the deletion on viral growth and reactivation from latency. Growth of the mutant viruses in NIH 3T3 cells was similar to that of wild-type virus. However, CXC chemokines with ELR motifs, KC, and macrophage-inflammatory protein 2, significantly increased viral replication of the wild-type, but not the mutant viruses, via a pertussis toxin-insensitive, mitogen-activated protein/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase-dependent pathway. IFN-gamma-inducible protein 10, a CXC chemokine lacking an ELR motif, was able to reverse the effect of KC on viral replication. The mutant viruses also showed significantly reduced reactivation from latently infected mouse splenocytes. Reinsertion of ORF74 into the mutant virus restored the wild-type phenotype. Utilizing a viral CXCR2 homologue to enhance replication and reactivation from latency represents a novel mechanism by which gammaherpesviruses can subvert the immune response.
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PMID:A gammaherpesvirus G protein-coupled receptor homologue is required for increased viral replication in response to chemokines and efficient reactivation from latency. 1249 6

beta-Arrestin 1 is required for internalization and mitogen-activated protein (MAP) kinase activation by the beta2 adrenergic receptor (beta2AR). Our previous studies have shown that chronic insulin treatment down-regulates cellular beta-arrestin 1 levels, leading to a marked impairment in G protein-coupled receptor and insulin-like growth factor-1 receptor-mediated MAP kinase and mitogenic signaling. In this study, we show that chronic insulin-treated, beta-arrestin 1depleted 3T3-L1 adipocytes display (i) increased isoproterenol-induced cAMP generation (53 +/- 38% at 1.5 min, 25 +/- 19% at 5 min, 63 +/- 14% at 30 min, and 59 +/- 2% at 60 min), a Galpha(s)-associated pathway; (ii) impaired isoproterenol-induced beta2AR internalization (reduced by 98 +/- 4%), which is required for MAP kinase signaling, a Galpha(i)-associated pathway; and (iii) increased beta-arrestin 1 phosphorylation at Ser-412. Taken together, these findings represent a hitherto unknown mechanism (degradation and phosphorylation of beta-arrestin, whereby the activation of the insulin receptor, belonging to the family of receptor tyrosine kinases, causes supersensitization of Galpha(s)-associated signaling and inhibition of Galpha(i)-associated signaling by the beta2AR, a prototypical G protein-coupled receptor.
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PMID:Beta -Arrestin 1 down-regulation after insulin treatment is associated with supersensitization of beta 2 adrenergic receptor Galpha s signaling in 3T3-L1 adipocytes. 1250 8

The metabotropic glutamate 1 (mGlu(1)) receptor in cerebellar Purkinje cells plays a key role in motor learning and motor coordination. Here we show that the G protein-coupled receptor kinases (GRK) 2 and 4, which are expressed in these cells, regulate the mGlu(1) receptor by at least in part different mechanisms. Using kinase-dead mutants in HEK293 cells, we found that GRK4, but not GRK2, needs the intact kinase activity to desensitize the mGlu(1) receptor, whereas GRK2, but not GRK4, can interact with and regulate directly the activated Galpha(q). In cells transfected with GRK4 and exposed to agonist, beta-arrestin was first recruited to plasma membranes, where it was co-localized with the mGlu(1) receptor, and then internalized in vesicles. The receptor was also internalized but in different vesicles. The expression of beta-arrestin V53D dominant negative mutant, which did not affect the mGlu(1) receptor internalization, reduced by 70-80% the stimulation of mitogen-activated protein (MAP) kinase activation by the mGlu(1) receptor. The agonist-stimulated differential sorting of the mGlu(1) receptor and beta-arrestin as well as the activation of MAP kinases by mGlu(1) agonist was confirmed in cultured cerebellar Purkinje cells. A major involvement of GRK4 and of beta-arrestin in agonist-dependent receptor internalization and MAP kinase activation, respectively, was documented in cerebellar Purkinje cells using an antisense treatment to knock down GRK4 and expressing beta-arrestin V53D dominant negative mutant by an adenovirus vector. We conclude that GRK2 and GRK4 regulate the mGlu(1) receptor by different mechanisms and that beta-arrestin is directly involved in glutamate-stimulated MAP kinase activation by acting as a signaling molecule.
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PMID:Role of G protein-coupled receptor kinase 4 and beta-arrestin 1 in agonist-stimulated metabotropic glutamate receptor 1 internalization and activation of mitogen-activated protein kinases. 1251 91

The discovery of the calcium-sensing receptor (CaR), a G protein-coupled receptor, has led to the elucidation of the pivotal roles of the CaR in systemic calcium homeostasis. The receptor is situated on the chief cells of the parathyroid glands, where it senses the extracellular Ca2+ concentration and in turn alters the rate of secretion of parathyroid hormone (PTH). The intracellular signal pathways to which the CaR couples include, but are not limited to, phospholipase C (PLC), and mitogen-activated protein kinases. The receptor is widely expressed in various tissues and likely serves important cellular functions beyond that of maintaining systemic calcium homeostasis. Functionally important mutations in the receptor have been found to cause disorders in calcium homeostasis due both to changes in the set point for PTH secretion and to the control of renal calcium excretion. These mutations cause hypercalcemia when the mutation inactivates the receptor and cause hypocalcemia when the mutation activates the receptor. Recent studies have revealed the presence of circulating autoantibodies to the calcium-sensing receptor in humans, with the clinical presentation the same as that for diseases caused by mutations in the CaR. In renal secondary hyperparathyroidism, a drug that stimulates the receptor (calcimimetic) shows great promise as a medical treatment for this condition.
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PMID:The calcium-sensing receptor in human disease. 1270 51

G protein-coupled receptors (GPCRs) initiate diverse down-stream signaling events in response to ligand stimulation, as rapid activation of the extracellular signal-regulated kinase ERK1 and ERK2. The chemokine monocyte chemoattractant protein-1 (MCP-1) is the agonist for several chemokine receptors that belong to the GPCR superfamily, CCR2 being the most important. Stimulation of mitogen-activated protein kinases (MAPKs) by MCP-1 has been implicated in integrin activation and chemotaxis, but the molecular pathways down-stream of the receptors remain unclear. To dissect the cascade of events leading to MAPK activation upon CCR2 receptor stimulation, several specific inhibitors and mutants of signal transduction proteins were used in monocytic cells endogenously expressing CCR2 and/or in human embryonic kidney-293 cells transfected with CCR2B receptors and epitope-tagged ERK1. We show that ERK activation by MCP-1 involves heterotrimeric Gi protein subunits, protein kinase C, phosphoinositide-3-kinase, and Ras. On the other hand, the activity of cytosolic tyrosine kinases, epidermal growth factor receptor transactivation, or variations in intracellular calcium levels are not required for the mitogenic activation elicited by MCP-1. In addition, we find that internalization of CCR2B itself is not necessary for efficient MCP-1-induced activation of ERK, although a dynamin mutant partially inhibits ERK stimulation. These results suggest that different parallel pathways are being activated that lead to the full activation of the mitogen-activated protein kinase cascade and that internalization of other signaling proteins but not of the receptor is required for complete ERK activation.
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PMID:Signaling pathways for monocyte chemoattractant protein 1-mediated extracellular signal-regulated kinase activation. 1292 Feb 15


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