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

---

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

Insulin and the insulin-like growth factors (IGF) I and II are structurally related peptides that elicit a large number of similar biological effects in target cells. Three well-characterized receptor complexes bind one or more of these peptides with high affinity. Two of these receptors, denoted as type I, are ligand-activated tyrosine kinases with similar heterotetrameric alpha 2 beta 2 subunit structures which bind insulin or IGF-I, respectively, with highest affinity. Ligand-stimulated tyrosine autophosphorylation of these receptors further activates their intrinsic tyrosine kinase activities both in vitro and in intact cells. Rapid signal transduction follows such receptor autophosphorylation and tyrosine kinase activation, leading to increased serine phosphorylation of many cellular proteins and decreased serine phosphorylation of several others. Experiments in our laboratory have identified three distinct insulin-activated serine kinase activities in cell-free extracts that appear to account for the insulin-stimulated serine phosphorylation of the insulin receptor itself, ATP citrate lyase, and acetyl CoA carboxylase, respectively. A third receptor in this group binds IGF-I and II, lacks kinase activity and is denoted as type II IGF receptor. Amino acid sequences of this receptor deduced from isolated rat cDNA clones show a high degree of homology with those of the bovine cation-independent mannose 6-phosphate (Man-6-P) receptor. We demonstrated that these receptors are indeed identical. The IGF-II/Man-6-P receptor rapidly recycles between the cell surface membrane and intracellular membrane compartments, providing for the rapid uptake of both IGF-II and mannose 6-phosphate-linked lysosomal enzymes. Insulin action markedly increases the proportion of receptors in the plasma membrane and the uptake of bound ligands. We also observe that large amounts of the extracellular domain of the IGF-II/Man-6-P receptor are released into the serum of fetal, neonatal and adult rats. The biological role of this receptor in IGF-II function is yet to be determined.
...
PMID:Multifunctional glycoprotein receptors for insulin and the insulin-like growth factors. 255 7

Since the studies on tyrosine phosphorylation of calmodulin by the insulin receptor kinase in vitro suggested that protamine and poly(L-lysine) may activate phosphorylation of the receptor beta subunit [Sacks & McDonald (1988) J. Biol. Chem. 263, 2377-2383], we examined the effects of a variety of basic polycations/proteins and polyamines on insulin receptor kinase activity. The insulin receptor purified from human placental membranes was incubated with each basic polycation/protein or polyamine and assayed for tyrosine-specific protein kinase activity by measuring 32P incorporation into the src-related peptide. At a concentration of 1 microM, poly(L-lysine) and poly(L-ornithine) markedly stimulated kinase activity, whereas poly(L-arginine) and histones H1 and H2B inhibited insulin receptor kinase. In contrast, at a concentration of 1 mM, three polyamines (spermine, spermidine and putrescine) did not alter kinase activity. Poly(L-lysine) and poly(L-ornithine) stimulated the insulin receptor kinase by 5-10-fold at concentrations of 0.1-1 microM. Protamine sulphate also showed a significant stimulatory effect at a concentration of 100 microM. Preincubation of the receptor with poly(L-lysine) or poly(L-ornithine) for 20-60 min resulted in maximal kinase activation. Poly(L-lysine), the most effective activator of the receptor kinase, was used to characterize further the mechanisms of the kinase activation. Poly(L-lysine) activates the insulin receptor kinase by increasing the Vmax. without changing the Km. Poly(L-lysine) markedly stimulates the kinase activity of insulin receptor preparations that have lost both basal kinase activity and the ability to be stimulated by insulin. Insulin and poly(L-lysine) also differed in their ability to stimulate the kinase activity of prephosphorylated receptors. Prephosphorylation of the receptors did not affect the stimulation of the kinase by insulin. In contrast, prephosphorylation of receptors resulted in a markedly enhanced ability of poly(L-lysine) to stimulate kinase activity. These studies suggest that the mechanisms by which poly(L-lysine) and insulin activate the kinase are different. In conjunction with other additional evidence, it is suggested that poly(L-lysine) interacts directly with the beta-subunit of the receptor, thereby activating the receptor kinase.
...
PMID:Effect of basic polycations and proteins on purified insulin receptor. Insulin-independent activation of the receptor tyrosine-specific protein kinase by poly(L-lysine). 255 12

The cell surface receptors for insulin and epidermal growth factor (EGF) both employ a tyrosine-specific protein kinase activity to fulfil their distinct biological roles. To identify the structural domains responsible for various receptor activities, we have generated chimeric receptor polypeptides consisting of major EGF and insulin receptor structural domains and examined their biochemical properties and cellular signalling activities. The EGF-insulin receptor hybrids are properly synthesized and transported to the cell surface, where they form binding competent structures that are defined by the origin of their extracellular domains. While their ligand binding affinities are altered, we find that these chimeric receptors are fully functional in transmitting signals across the plasma membrane and into the cell. Thus, EGF receptor and insulin receptor cytoplasmic domain signalling capabilities are independent of their new heterotetrameric or monomeric environments respectively. Furthermore, the cytoplasmic domains carry the structural determinants that define kinase specificity, mitogenic and transforming potential, and receptor routing.
...
PMID:Cytoplasmic domains determine signal specificity, cellular routing characteristics and influence ligand binding of epidermal growth factor and insulin receptors. 258 88

The insulin receptor, a glycoprotein consisting of two extracellular alpha- and two transmembrane beta-subunits, is thought to mediate hormone action by means of its tyrosine-specific protein kinase activity. To explore the mechanism of insulin receptor phosphorylation we have used NIH3T3 cells transfected with two receptor constructs: one encoding a chimeric receptor composed of the extracellular domain of the human EGF receptor and the cytosolic domain of the human insulin receptor beta-subunit, and a second construct encoding a kinase-defiecient human insulin receptor. Stimulation of these cells with EGF induced tyrosine autophosphorylation of the EGF-insulin receptor chimera (150 kd) and tyrosine phosphorylation of the beta-subunit of the kinase-deficient insulin receptor (95 kd). The phosphopeptides of the autophosphorylated cytoplasmic domain of the EGF-insulin receptor chimera were comparable to those of the transphosphorylated beta-subunit of the kinase-deficient insulin receptor and of the wild-type human insulin receptor. When immunoaffinity purified EGF-insulin receptor hybrids and kinase-deficient insulin receptors were used in a cell lysate phosphorylation assay, it was found that addition of EGF produced 32P-labeling of both receptor species. We conclude that EGF acting directly through the EGF-insulin receptor chimera causes transphosphorylation of the kinase-deficient insulin receptor. These data support the notion that autophosphorylation of the insulin receptor may proceed by an intermolecular mechanism.
...
PMID:Intermolecular transphosphorylation between insulin receptors and EGF-insulin receptor chimerae. 258

Aggregation and autophosphorylation of the insulin receptor-protein kinase, from cultured 3T3-L1 adipocytes, were studied in the presence of cationic polyamino acids. Poly-L-lysine and poly-L-arginine produced the following effects with the purified receptor: first, the autophosphorylation rate was increased by polycations. Half-maximal stimulation was proportional to polymer length. The rate enhancement was greater at lower ATP concentrations. Second, near-endpoint (equilibrium) autophosphorylation was greater in the presence of the polycations. Polycations inhibited the reverse reaction: ADP + phosphoreceptor yielding ATP + aporeceptor. Third, the [32P]phosphopeptides generated by trypsin digestion of the 32P-beta-subunit, showed that no new autophosphorylation sites resulted from the presence of polycations. Fourth, the polycations, but not insulin, promoted receptor aggregation, and phosphoreceptor aggregated more readily than aporeceptor. Insulin receptor enriched through the wheat germ agglutinin eluate step was compared with purified receptor. Higher concentrations of poly-L-arginine were required to stimulate autophosphorylation and to promote aggregation. Finally, several polycation-dependent substrates present in the wheat germ agglutinin eluate co-aggregated with the insulin receptor. Polycation-stimulated receptor autophosphorylation is linked to a lower KM,app for ATP, but substrate phosphorylation may require the aggregation.
...
PMID:Insulin receptor aggregation and autophosphorylation in the presence of cationic polyamino acids. 259 62

Examination of 125I-IGF-1 affinity cross-linking and beta-subunit autophosphorylation has indicated that IGF-1 induces a covalent association of isolated alpha beta heterodimeric IGF-1 receptors into an alpha 2 beta 2 heterotetrameric state, in a similar manner to that observed for the insulin receptor [Morrison, B.D., Swanson, M.L., Sweet, L.J., & Pessin, J.E. (1988) J. Biol. Chem. 263, 7806-7813]. The formation of the alpha 2 beta 2 heterotetrameric IGF-1 receptor complex from the partially purified alpha beta heterodimers was time dependent with half-maximal formation in approximately 30 min at saturating IGF-1 concentrations. The IGF-1-dependent association of the partially purified alpha beta heterodimers into an alpha 2 beta 2 heterotetrameric state was specific for the IGF-1 receptors since IGF-1 was unable to stimulate the protein kinase activity of the purified alpha beta heterodimeric insulin receptor complex. Incubation of the alpha 2 beta 2 heterotetrameric IGF-1 holoreceptor with the specific sulfhydryl agent iodoacetamide (IAN) did not alter 125I-IGF-1 binding of IGF-1 stimulation of protein kinase activity. In addition, IAN did not affect the Mn/MgATP-dependent noncovalent association of IGF-1 receptor alpha beta heterodimers into an alpha 2 beta 2 heterotetrameric state. However, IAN treatment of the alpha beta heterodimeric IGF-1 receptors inhibited the IGF-1-dependent covalent formation of the disulfide-linked alpha 2 beta 2 heterotetrameric complex. These data indicate that IGF-1 induces the covalent association of isolated alpha beta heterodimeric IGF-1 receptor complexes into a disulfide-linked alpha 2 beta 2 heterotetrameric state whereas Mn/MgATP induces a noncovalent association.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:IGF-1-dependent subunit communication of the IGF-1 holoreceptor: interactions between alpha beta heterodimeric receptor halves. 261 Dec 57

Xenopus laevis oocytes possess a glucose transport system that is activated 3- to 5-fold by insulin-like growth factor I (Ka = 3 nM) and insulin (Ka = 200-250 nM), properties suggesting activation mediated by an insulin-like growth factor I receptor. This activation increases the Vmax of hexose uptake and has little or no effect on the Km for deoxyglucose (Km = 1-2 mM). Activation by hormone requires about 60 min and is inhibited by cytochalasin B but not by cycloheximide. The dependence of hexose uptake rate on hexose concentration exhibits cooperativity with Hill coefficients of 1.8 and 1.4 for the basal and hormone-activated states, respectively. Microinjection of a monoclonal antibody directed against the tyrosine kinase domain of the human insulin receptor blocks activation of hexose uptake by insulin-like growth factor I and insulin but has no effect on basal uptake. Taken together the results implicate the tyrosine-specific protein kinase activity of a cell-surface insulin-like growth factor I receptor in the activation of glucose transport in the Xenopus oocyte.
...
PMID:Activation of glucose uptake by insulin and insulin-like growth factor I in Xenopus oocytes. 264 87

A kinase-splitting membranal proteinase specifically clips the cytoplasmic moiety of the insulin receptor beta-subunit (95 kd) to yield an 84-kd fragment. Using antibodies against different domains in the receptor, cleavage is shown to remove an 11-kd 'tail' (rooted at the C-terminal end of the kinase domain) which includes tyrosines 1316 and 1322. This cleavage impairs the ability of the clustered tyrosines 1146, 1150 and 1151 to undergo autophosphorylation. Nevertheless, the clipped beta-subunit is as active as the intact subunit if its kinase activity is measured at high exogenous substrate concentrations (greater than or equal to 2 mg/ml) indicating that autophosphorylation is not obligatory for insulin-dependent phosphotransferase activity. With low substrate concentrations (e.g. 0.2 mg/ml) a severe damage to the kinase activity is detected, which may reflect an important structural contribution of the 'tail' and/or the clustered phosphotyrosines in creating the preferential affinity of the kinase for its in vivo substrate(s). The membranal proteinase strictly recognizes the native conformation of the kinase domain, and fails to cleave it after denaturation. Since such a conformation-dependent cleavage occurs also in the case of the cytoplasmic moiety of the EGF receptor and the catalytic subunit of cAMP-dependent protein kinase, it is suggested that the similarity between these three kinase domains extends beyond their reported sequence homology to reflect a similarity in conformation.
...
PMID:Studying the structure of the intracellular moiety of the insulin receptor with a kinase-splitting membranal proteinase. 265 55

To investigate myeloid cell maturation, we established a panel of monoclonal antibodies that recognize myeloid cell nuclear antigens. One of these monoclonal antibodies was used to purify a specific protein complex (PC) from a human spleen. This PC, which is present at high levels in peripheral blood monocytes and granulocytes, contains a protein that is the cystic fibrosis (CF) antigen. The purified PC was shown to inhibit the activity of casein kinase I and II but not cAMP-dependent protein kinase, protein kinase C, v-abl tyrosine kinase, or insulin receptor tyrosine kinase. The observed Ki values for casein kinases I and II purified from several sources were 1 microM or less. Furthermore, the addition of the purified PC to a nuclear extract from human cells was able to prevent protein kinase-mediated stimulation of RNA polymerase activity. The unique inhibitory character of the PC and its elevated levels in monocytes and granulocytes and of the CF antigen in CF patients implies that this complex may be associated with myeloid cell functions and perhaps with the cause or consequence of the clinical manifestations of CF.
...
PMID:A protein containing the cystic fibrosis antigen is an inhibitor of protein kinases. 265 77

As an initial attempt to identify early steps in insulin action that may be involved in the growth responses of neurons to insulin, we investigated whether insulin receptor activation increases the phosphorylation of ribosomal protein S6 in cultured fetal neurons and whether activation of a protein kinase is involved in this process. When neurons were incubated for 2 h with 32Pi, the addition of insulin (100 ng/ml) for the final 30 min increased the incorporation of 32Pi into a 32K microsomal protein. The incorporation of 32Pi into the majority of other neuronal proteins was unaltered by the 30-min exposure to insulin. Cytosolic extracts from insulin-treated neurons incubated in the presence of exogenous rat liver 40S ribosomes and [gamma-32P]ATP displayed a 3- to 8-fold increase in the phosphorylation of ribosomal protein S6 compared to extracts from untreated cells. Inclusion of cycloheximide during exposure of the neurons to insulin did not inhibit the increased cytosolic kinase activity. Activation of S6 kinase activity by insulin was dose dependent (seen at insulin concentration as low as 0.1 ng/ml) and reached a maximum after 20 min of incubation. Addition of phosphatidylserine, diolein, and Ca2+ to the in vitro kinase reaction had no effect on the phosphorylation of ribosomal protein S6. Likewise, treatment of neurons with (Bu)2cAMP did not alter the phosphorylation of ribosomal protein S6 by neuronal cytosolic extracts. We conclude that insulin activates a cytosolic protein kinase that phosphorylates ribosomal S6 in neurons and is distinct from protein kinase-C and cAMP-dependent protein kinase. Stimulation of this kinase may play a role in insulin signal transduction in neurons.
...
PMID:Insulin receptors mediate growth effects in cultured fetal neurons. II. Activation of a protein kinase that phosphorylates ribosomal protein S6. 266 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---