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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of mouse colliculi neurons to selective 5-hydroxytryptamine (5-HT)4 agonists was accompanied by a rapid desensitization of the receptor-stimulated adenylyl cyclase response. Half-maximal desensitization occurred after 2 min. Only exposure of neurons to selective 5-HT4 agonists led to a potent desensitization of the 5-HT4-mediated response. Neurons exposed to other agents, like isoproterenol, vasoactive intestinal peptide, or forskolin, that increase cAMP levels did not undergo any desensitization of 5-HT4 receptors. Activation of protein kinase A with either 8-bromo-cAMP or dibutyryl-cAMP or application of inhibitors of protein kinase A-dependent phosphorylation did not change the rate of 5-HT4-induced desensitization. No shift to lower potency of 5-HT4 agonists in the concentration-response curve was observed. These results suggest that 5-HT4 receptor agonists induced homologous but not cAMP-mediated heterologous desensitization. A good correlation was found between the affinities of nine 5-HT4 agonists and their abilities to desensitize the adenylyl cyclase response. This may indicate that homologous desensitization is a function of the mean occupancy time of the receptors by agonists. When permeabilized neurons were loaded with heparin, an inhibitor of the beta-adrenergic receptor kinase (beta ARK), 5-HT4 receptor desensitization was reduced by 30-40%. Interestingly, Zn2+, an other inhibitor of beta ARK, totally prevented 5-HT4-induced desensitization. Pretreatment of neurons with concanavalin A, reported to inhibit sequestration of beta-adrenergic receptors from the cell surface, reduced the desensitization process by 70%. These data suggest that both sequestration and phosphorylation by beta ARK, or another specific agonist-dependent receptor kinase, are involved in homologous desensitization of 5-HT4 receptors coupled to adenylyl cyclase.
Mol Pharmacol 1992 Nov
PMID:Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons. 133 63

The intrinsic tyrosyl kinase activity of the insulin receptor is regulated by a balance between insulin-induced receptor autophosphorylation, which stimulates the receptor kinase, and enzymatic dephosphorylation of the receptor, which deactivates its kinase activity. The cellular protein-tyrosine phosphatase (PTPase) enzymes responsible for reversing the activated state of the insulin receptor have not been characterized. Our laboratory is interested in identifying and cloning the specific PTPase(s) that regulate the phosphorylation state of the insulin receptor. This chapter will summarize the design and results of our initial molecular cloning studies to identify specific PTPases in insulin-sensitive tissues that may have a potential physiological role in insulin action and clinical insulin resistance.
Mol Cell Biochem 1992 Feb 12
PMID:Approaches to the molecular cloning of protein-tyrosine phosphatases in insulin-sensitive tissues. 162 76

A chimeric receptor composed of the extracellular domain of the human T-cell antigen CD2 (T11) joined to the membrane-spanning segment and the intracellular tyrosine kinase domain of the human colony-stimulating factor 1 receptor (CSF-1R) was expressed in murine NIH 3T3 fibroblasts. Stimulation of these cells with monoclonal antibodies to CD2 induced phosphorylation of the chimeric glycoprotein on tyrosine, receptor downmodulation, and mitogenesis. In contrast, neither human CSF-1R nor the chimeric receptor was able to function in interleukin-2-dependent murine T cells. In fibroblasts, then, CSF-1 per se is not required for activation of the receptor kinase or for a biological response, whereas in T cells, CSF-1R may be unable to engage the downstream signal transduction machinery.
Mol Cell Biol 1990 May
PMID:Antibody-induced mitogenicity mediated by a chimeric CD2-c-fms receptor. 169 41

Insulin internalization and degradation, insulin receptor internalization and recycling, as well as long term receptor down-regulation were comparatively studied in Chinese hamster ovary (CHO) cell lines, either parental or expressing the wild-type human insulin receptor (CHO.R) or a mutated receptor in which the tyrosine residues in positions 1162 and 1163 were replaced by phenylalanines (CHO.Y2). The two transfected cell lines presented very similar binding characteristics, and their pulse labeling with [35S]methionine revealed that the receptors were processed normally. As expected, the mutation of these twin tyrosines resulted in a defective insulin stimulation of both receptor kinase activity and glycogen synthesis. We now present evidence that compared to CHO.R cells, which efficiently internalized and degraded insulin, CHO.Y2 cells exhibited a marked defect in hormone internalization, leading to impaired insulin degradation. Moreover, the mutated receptors were found to be less effective than the wild-type receptors in transducing the hormone signal for receptor internalization, whereas the process of receptor recycling after internalization seemed not to be altered. In parental CHO cells, insulin induced long term receptor down-regulation, but was totally ineffective in both transfected cell lines. These results reveal that the tyrosines 1162 and 1163 in the kinase regulatory domain of the receptor beta-subunit play a pivotal role in insulin and receptor internalization.
Mol Endocrinol 1990 Feb
PMID:Mutation of tyrosine residues 1162 and 1163 of the insulin receptor affects hormone and receptor internalization. 218 49

The erbB-2 gene product, gp185erbB-2, displays a potent transforming effect when overexpressed in NIH 3T3 cells. In addition, it possesses constitutively high levels of tyrosine kinase activity in the absence of exogenously added ligand. In this study, we demonstrate that its carboxy-terminal domain exerts an enhancing effect on erbB-2 kinase and transforming activities. A premature termination mutant of the erbB-2 protein, lacking the entire carboxy-terminal domain (erbB-2 delta 1050), showed a 40-fold reduction in transforming ability and a lowered in vivo kinase activity for intracellular substrates. When the carboxy-terminal domain of erbB-2 was substituted for its analogous region in the epidermal growth factor receptor (EGFR) (EGFR/erbB-2COOH chimera), it conferred erbB-2-like properties to the EGFR, including transforming ability in the absence of epidermal growth factor, elevated constitutive autokinase activity in vivo and in vitro, and constitutive ability to phosphorylate phospholipase C-gamma. Conversely, a chimeric erbB-2 molecule bearing an EGFR carboxy-terminal domain (erbB-2/EGFRCOOH chimera) showed reduced transforming and kinase activity with respect to the wild-type erbB-2 and was only slightly more efficient than the erbB-2 delta 1050 mutant. Thus, we conclude that the carboxy-terminal domains of erbB-2 and EGFR exert different regulatory effects on receptor kinase function and biological activity. The up regulation of gp185erbB-2 enzymatic activity exerted by its carboxy-terminal domain can explain, at least in part, its constitutive level of kinase activity.
Mol Cell Biol 1990 Jun
PMID:The carboxy-terminal domains of erbB-2 and epidermal growth factor receptor exert different regulatory effects on intrinsic receptor tyrosine kinase function and transforming activity. 218 97

Insulin and insulinlike growth factor 1 (IGF-1) receptors are present in brain, yet their function remains obscure. Expression of these tyrosine kinase-bearing growth factor receptors during rat brain development was examined by using three antipeptide antibodies directed against epitopes in the beta subunits (AbP2, AbP4, and AbP5). All three antibodies recognized both insulin and IGF-1 receptors. Membranes were prepared from fetal brains (14 to 21 days of gestation), neonatal brain (postnatal day 1), and adult brain. Immunoblot analyses using AbP4 and AbP5 revealed a 92-kilodalton (kDa) protein that corresponded to the beta subunit of the insulin and IGF-1 receptors. Densitometric scanning of immunoblots indicated that receptor proteins were 4- to 10-fold more abundant in fetal brain membranes than in membranes from adult brain. Expression was highest during 16 to 18 days of gestation and declined thereafter to the relatively low level found in adult brain. Immunoblot analyses with AbP2 as well as ligand-activated receptor autophosphorylation revealed an additional protein of 97 kDa. This protein was phosphorylated in response to IGF-1 and was not directly recognized by AbP4 or AbP5. The covalent association of the 97-kDa protein with the 92-kDa beta subunit was indicated by the ability of AbP4 and AbP5 to immunoprecipitate both proteins under nonreducing conditions but only the 92-kDa protein after reduction. In contrast, AbP2 immunoprecipitated both proteins regardless of their association. This immunospecificity remained unchanged after deglycosylation of the isolated proteins. Two-dimensional tryptic phosphopeptide analysis showed that the 92- and 97-kDa subunits of the IGF-1 receptor are related but distinct proteins. Taken together, the data suggest that the 92- and 97-kDa subunits differ in primary amino acid sequence. Thus, two distinct beta subunits may be present in a single IGF-1 receptor in brain. These subunits have in common an epitope recognized by an antibody to the tyrosine kinase domain (AbP2) but differ in regions thought to be important in receptor kinase regulation and signal transduction.
Mol Cell Biol 1989 Jul
PMID:Insulin and insulinlike growth factor 1 (IGF-1) receptors during central nervous system development: expression of two immunologically distinct IGF-1 receptor beta subunits. 247 58

Promising progress in understanding the molecular basis of insulin action has been achieved by demonstrating that the insulin receptor is an insulin-sensitive tyrosine kinase. Here we discuss the structure of this receptor kinase and compare it with receptors for related growth factors. We review the known modes to regulate the receptor kinase activity, either through its autophosphorylation (on tyrosine residues) or through its phosphorylation by other kinases (on serine and threonine residues). We discuss the role of the receptor kinase activity in hormone signal transduction in light of results indicating a reduced kinase activity in insulin-resistant states. Finally, studies to identify natural substrates for the insulin receptor kinase are presented. The possible physiological role of these phosphorylated substrates in mediating insulin action is evaluated.
Crit Rev Biochem Mol Biol 1989
PMID:The insulin receptor: structure and function. 254 71

Studies investigating the effects of beta-naphthoflavone (beta NF) on insulin receptor binding and its intrinsic protein kinase activity in rat liver and placenta were performed. Membranes were prepared from maternal liver and placenta on gestation day 11 and used for [125I]insulin radioreceptor assay. Scatchard analysis showed that association constants (Ka) for high affinity binding sites were similar for placental and liver membrane. The administration of beta NF, 15 mg/kg, 1 day before study did not alter the specific binding of insulin to liver membranes, whereas ligand binding to placental preparations was decreased 40% from control. Scatchard analysis of binding to placental membranes suggests that beta NF treatment was associated with a change in the number of high affinity binding sites. In further studies membrane receptors were solubilized and partially purified by wheat germ agglutinin affinity chromatography for protein kinase assay. Insulin stimulated the phosphorylation of the Mr 95,000 subunit of the receptor in lectin-purified membrane proteins from liver and placenta. In liver receptor preparations, beta NF treatment was associated with a nearly 3-fold increase in the insulin-stimulated phosphorylation of the 95-kD protein. In contrast, placental receptor preparations showed a 40% decrease in the extent of autophosphorylation following beta NF treatment. Insulin-stimulated phosphorylation of an exogenous substrate poly(Glu4, Tyr) also showed a divergent pattern of changes in liver and placental receptors following beta NF treatment. In studies during late gestation (day 18), beta NF treatment was also associated with an increase in liver receptor kinase activity, whereas placental receptors showed a decrease in autophosphorylation. Thus, acute treatment with beta NF during mid and late gestation was associated with significant alterations in insulin receptor protein kinase activity, and data suggest that fetal insulin receptors may respond in a different manner than maternal receptors to polyaromatic compounds like beta NF. The observed effects of beta NF on liver and placental receptor kinase activity may be related to alterations in insulin function in the regulation of pregnancy and fetoplacental growth.
Mol Pharmacol 1988 Mar
PMID:Effects of beta-naphthoflavone on insulin receptor binding and protein kinase activity in rat liver and placenta. 283 20

Three types of mutations were introduced into the platelet-derived growth factor (PDGF) receptor to cause a loss of PDGF-stimulated tyrosine kinase activity: (i) a point mutation of the ATP-binding site, (ii) a deletion of the carboxyl-terminal region, and (iii) replacement of the membrane-spanning sequences by analogous transmembrane sequences of other receptors. Transfectants expressing mutated receptors bind, 125I-labeled PDGF with a high affinity but had no PDGF-sensitive tyrosine kinase activity, phosphatidylinositol turnover, increase in the intracellular calcium concentration, change in cellular pH, or stimulation of DNA synthesis. However, PDGF-induced receptor down regulation was normal in the mutant cells. These results indicate that the transmembrane sequence has a specific signal-transducing function other than merely serving as a membrane anchor and that the receptor kinase activity is necessary for most responses to PDGF but is not required for receptor down regulation.
Mol Cell Biol 1988 Dec
PMID:Role of tyrosine kinase and membrane-spanning domains in signal transduction by the platelet-derived growth factor receptor. 285 92

The metal: ATP characteristics of insulin- and epidermal growth factor-(EGF)-stimulated protein kinase activities were examined in Nonidet P40 extracts of rat liver plasma membranes. The two kinase activities were capable of utilizing either manganese or magnesium, although differences were observed. Insulin-stimulated 32P incorporation into an Mr 95 000 protein exhibited a higher affinity for ATP in the presence of manganese compared to magnesium. At 200 microM ATP, insulin stimulated 32P incorporation into the Mr 95 000 protein 3- to 5-fold after 5 min in the presence of either metal. At 1 mM ATP, insulin-stimulated 32P incorporation was significantly greater in the presence of magnesium. In contrast, EGF-stimulated 32P incorporation into an Mr 170 000 protein exhibited similar ATP dependencies in the presence of magnesium or manganese. Basal phosphorylation of the Mr 170 000 protein was 2- to 3-fold higher in the presence of manganese, however. Since the higher basal phosphorylation persisted after chromatography on wheat germ lectin-Sepharose, it may represent an inherent activity of the receptor kinase. In the presence of magnesium: ATP, low concentrations of manganese enhanced both insulin- and EGF-stimulated phosphorylation of angiotensin II suggesting involvement of a second metal binding site which regulates the kinase activity. The results presented show major differences in the metal: ATP properties of the two major hormonally regulated protein kinase activities observed in detergent-extracted liver membranes.
Mol Cell Endocrinol 1986 Sep
PMID:Metal: ATP characteristics of insulin- and epidermal growth factor-stimulated phosphorylation in detergent extracts of rat liver plasma membranes. 352 12


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