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)

Lymphocyte membrane fractions from both normal and neoplastic sources exhibit tyrosine-specific protein kinase activity. The molecular weights of the endogenous substrates phosphorylated on tyrosine residues differ in B and T cells. To further characterize membrane tyrosine phosphorylation in the two major classes of lymphocytes, the tryptic phosphopeptides of their endogenous substrates were compared and the sensitivity of the kinases to inhibition by N alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) was determined. The two major B cell substrates (61,000 and 55,000 daltons, p61 and p55) were gel purified after phosphorylation and exhaustively digested with trypsin. Separation by reverse phase high pressure liquid chromatography demonstrated that these two substrates had two identical phosphotyrosine containing tryptic phosphopeptides. p61 had an additional phosphotyrosine site. Parallel analysis of the two T cell substrates (64,000 and 58,000 daltons, p64 and p58) showed that they also contained two phosphotyrosine sites that were identical. However, the tryptic phosphopeptides from the B and T cell substrate pairs were clearly distinct suggesting that they arise from different gene products. When B and T cell membrane fractions were preincubated with TLCK (21 degrees C, 30 min) a dose-dependent decrease in p64 and p58 phosphorylation resulted. p61 and p55 phosphorylation was not affected at concentrations up to 10 mM TLCK. Tyrosine-specific kinase activity was also assessed by measuring phosphorylation of a tyrosine containing synthetic peptide. The kinase activity of T cell plasma membrane fractions was inhibited by TLCK; the B cell activity was unaffected. The results suggest that membrane fractions from normal and some neoplastic B and T cells have at least two different tyrosine-specific kinases.
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PMID:Characterization of distinct tyrosine-specific protein kinases in B and T lymphocytes. 388 8

We have found that the beta-subunit of the insulin receptor is a phosphoprotein and that the degree of phosphorylation is increased by the binding of insulin to its receptor. Furthermore we have found that the beta-subunit of the insulin receptor itself is a tyrosine-specific protein kinase. Tyrosine-specific protein kinases have been reported to be associated with the transforming gene product of RNA tumor viruses, the EGF receptor, the IGF-I receptor and a protein believed to be the receptor for PDGF. These findings suggest that determination of the endogenous substrated for these tyrosine-specific protein kinases may yield a sequence of regulatory proteins for cell growth and transformation. From this point of view, our recent findings that the purified insulin receptor-kinase can phosphorylate purified microtubule protein (tubulin, MAP2, tau) are interesting.
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PMID:[Phosphorylation of the receptor insulin and insulin-like growth factors]. 388 59

Tyrosine-specific protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37) activity was measured in normal human nonadherent peripheral blood lymphocytes using synthetic peptide substrates having sequence homologies with either pp60src or c-myc. A high level of tyrosine-specific protein kinase activity was found associated with the cell particulate fraction (100 000 X g pellet). High-pressure liquid chromatography and phosphoamino acid analysis of the synthetic peptide substrates substantiated the phosphorylation of tyrosine residues by the particulate fraction enzyme. The human enzyme was also capable of phosphorylating a synthetic random polymer of 80% glutamic acid and 20% tyrosine. Enzyme activity was half-maximal with 22 microM Mg X ATP and had apparent Km values for the synthetic peptides from 1.9 to 7.1 mM. The enzyme preferred Mg2+ to Mn2+ for optimal activity and was stimulated 2-5-fold by low levels (0.05%) of some ionic as well as non-ionic detergents including deoxycholate, Nonidet P-40 and Triton X-100. The enzyme activity was not stimulated by N6;O2'-dibutyryl cyclic AMP (100 microM), N6;O2'-dibutyryl cyclic GMP (100 microM), Ca2+ (200 microM), insulin (1 microgram/ml) or homogeneous human T-cell growth factor (3 micrograms/ml) under the conditions used. Alkaline-resistant phosphorylation of particulate proteins in vitro revealed protein bands with Mr 59 000 and 54 000 suggesting that there are endogenous substrates for the human lymphocyte tyrosine protein kinase.
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PMID:High tyrosine-specific protein kinase activity in normal human peripheral blood lymphocytes. 403 88

Tyrosine-specific protein kinases from normal tissue have been studied using synthetic peptides as substrate. Spleen had much higher activity of the enzyme in the particulate fraction than any other normal tissue (except purified T lymphocytes). The tyrosine protein kinase from the particulate fraction of rat spleen was partially purified and characterized. The kinase could phosphorylate src-related as well as unrelated peptides and casein at tyrosine residues. The enzyme in the membrane seemed to have somewhat different substrate specificity than the solubilized, partially purified enzyme. Serum containing antibody to pp60v-src did not precipitate the kinase; however, the protein kinase could phosphorylate the heavy chain of IgG from TBR serum (but not from normal serum). The possible relationship of the tyrosine-specific protein kinase of spleen with pp60c-src and other tyrosine-specific protein kinases is discussed.
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PMID:Tyrosine-specific protein kinases of normal tissues. 643 59

Intercellular adhesion molecules (ICAM)-1 and -3 coexist on T lymphocytes and are counter-receptors for the integrin LFA-1. Signaling through ICAM-3 stimulates a number of T cell functions and involves phosphorylation of Fyn, Lck, CD45, and other proteins. In contrast, this type of specific signaling event has not been described for signaling through ICAM-1. Here, tyrosine phosphorylation of cellular proteins was examined after cross-linking of ICAM-1. Tyrosine phosphorylation of the 34-kDa cdc2 protein kinase was induced transiently after stimulation of the leukemic T cell line, Molt-3, or peripheral blood T cells. Stimulation through ICAM-1 had no effect on constitutive presence of cdc2 or phosphorylation of cdc2 on threonine. cdc2 kinase activity was constitutive in peripheral blood T cells, and transient inhibition of kinase activity after ICAM-1 stimulation correlated kinetically with phosphorylation of cdc2 on tyrosine.
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PMID:Cross-linking of ICAM-1 on T cells induces transient tyrosine phosphorylation and inactivation of cdc2 kinase. 749 27

Angiotensin II induces protein tyrosine kinase activation and apparent decreased electrophoretic mobility of the c-raf-1 serine/threonine protein kinase in cultured rat vascular smooth muscle cells. Tyrosine phosphorylation of at least 9 cellular proteins with molecular weights of 151, 131, 116, 110, 90, 65, 62, 60, 52 kd was induced in a time- and concentration-dependent manner, and included a serine/threonine protein kinase. The phosphotyrosine containing proteins differed from those induced by PDGF BB or AB. Angiotensin II by itself was shown not to act as a mitogen in cultured smooth muscle cells.
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PMID:Angiotensin II mediates intracellular signalling in vascular smooth muscle cells by activation of tyrosine-specific protein kinases and c-raf-1. 750 74

Tyrosine kinases catalyze phosphoryl transfers from ATP to tyrosine residues in proteins. Despite their growing importance, their kinetic mechanism has remained largely unexplored. In this study, we have investigated the tyrosine kinase reaction catalyzed by purified human recombinant Csk (C-terminal Src kinase). Poly(Glu,Tyr) 4:1 was used as the tyrosine-containing substrate. Both ATP and poly(Glu,Tyr) were shown to be well behaved saturable substrates for recombinant Csk, with Km values that were in reasonable agreement with literature values reported for the non-recombinant enzyme and with kcat about 40 min-1. A sequential kinetic mechanism is suggested by a steady state kinetic analysis. Inhibitor studies with ADP and beta,gamma-imidoadenosine 5'-triphosphate were performed, and these results provided evidence against the possibility that ordered binding of peptide prior to ATP occurs. While a suitable competitive inhibitor of poly(Glu,Tyr) has not yet been identified, other evidence pointed to a rapid equilibrium random mechanism. Csk utilized adenosine 5'-O-(3-thiotriphosphate) in place of ATP. The phosphorothioyl transfer occurred with a kcat about 15-20-fold lower than the ATP reaction but with similar Km values. Deuterium solvent isotope effects on kcat were small for both reactions in a pH-independent range, consistent with the possibility that proton transfer is asymmetric in the reaction transition state. Using viscosity effects, ADP product release was suggested to be partially rate determining for catalysis in the standard ATP reaction. A comparison of the Csk kinetic mechanism with that of protein kinase A is discussed.
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PMID:Evaluation of the catalytic mechanism of recombinant human Csk (C-terminal Src kinase) using nucleotide analogs and viscosity effects. 752 38

The M(r) 38,000 RNA-binding protein (P38) is the major component of translationally repressed messenger ribonucleoproteins in cryptobiotic gastrulae of the brine shrimp Artemia. Partial elucidation of the amino acid sequence of P38 reveals that it is homologous to A/B-type hnRNP proteins. This was confirmed by immunodetection with antibodies specific for A/B-type hnRNP proteins from Drosophila melanogaster. P38 can be phosphorylated in vitro by a src-related protein tyrosine kinase on multiple tyrosine residues located predominantly in the glycine-rich domain. Tyrosine phosphorylated P38 can be efficiently dephosphorylated by a specific protein tyrosine phosphatase (1B-like) and by protein phosphatase 2A activated by the phosphotyrosyl phosphatase activator. Tyrosine phosphorylation of P38 slightly influences its subsequent phosphorylation by casein kinase II. The latter phosphorylation site is located in the glycine-rich domain of P38. Two-dimensional gel electrophoresis resolves P38 into multiple isoforms which shift to more acidic pI values after phosphorylation by protein tyrosine kinase or casein kinase II. From nitrocellulose filter binding and UV cross-linking analysis, evidence was obtained that tyrosine phosphorylation of P38 impairs its binding to poly(A) but not to poly(U). This demonstrates the involvement of tyrosine residues in polynucleotide-specific RNA binding that can be regulated by phosphorylation/dephosphorylation.
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PMID:Tyrosine phosphorylation of a M(r) 38,000 A/B-type hnRNP protein selectively modulates its RNA binding. 752 88

Focal adhesion kinase (FAK) is a widely expressed nonreceptor protein-tyrosine kinase implicated in integrin-mediated signal transduction pathways and in the process of oncogenic transformation by v-Src. Elevation of FAK's phosphotyrosine content, following both cell adhesion to extracellular matrix substrata and cell transformation by Rous sarcoma virus, correlates directly with an increased kinase activity. To help elucidate the role of FAK phosphorylation in signal transduction events, we used a tryptic phosphopeptide mapping approach to identify tyrosine sites of phosphorylation responsive to both cell adhesion and Src transformation. We have identified four tyrosines, 397, 407, 576, and 577, which are phosphorylated in mouse BALB/3T3 fibroblasts in an adhesion-dependent manner. Tyrosine 397 has been previously recognized as the major site of FAK autophosphorylation. Phosphorylation of tyrosines 407, 576, and 577, which are previously unrecognized sites, is significantly elevated in the presence of c-Src in vitro and v-Src in vivo. Tyrosines 576 and 577 lie within catalytic subdomain VIII--a region recognized as a target for phosphorylation-mediated regulation of protein kinase activity. We found that maximal kinase activity of FAK immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of FAK by Src (or other Src family kinases) is an important step in the formation of an active signaling complex.
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PMID:Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. 752 76

Most neurotransmitter receptors examined to date are either regulated by phosphorylation or contain consensus sequences for phosphorylation by protein kinases. The nicotinic acetylcholine receptor (AChR), which mediates depolarization at the neuromuscular junction, has served as a model for the study of the structure, function, and regulation of ligand-gated ion channels. The AChR is phosphorylated by protein kinase A, protein kinase C, and an unidentified protein tyrosine kinase. Tyrosine phosphorylation of the AChR is correlated with a modulation of the rate of receptor desensitization and is associated with AChR clustering. We showed that agrin, a neuronally derived extracellular matrix protein, induces AChR clustering and tyrosine phosphorylation. In addition, we identified two protein tyrosine kinases, Fyn and Fyk, that appear to be involved in the regulation of synaptic transmission at the neuromuscular junction by phosphorylating the AChR. The two kinases are highly expressed in Torpedo electric organ, a tissue enriched in synaptic components including the AChR. As demonstrated by coimmunoprecipitation, Fyn and Fyk associate with the AChR. Furthermore, the AChR is phosphorylated in Fyn and Fyk immunoprecipitates. We investigated the molecular basis for the association of the AChR with Fyn and Fyk using fusion proteins derived from the kinases. The AChR bound specifically to the SH2 domain fusion proteins of Fyn and Fyk. The association of the AChR with the SH2 domains is dependent on the state of AChR tyrosine phosphorylation and is mediated by the delta subunit of the receptor. These data provide evidence that the protein tyrosine kinases Fyn and Fyk may act to phosphorylate the AChR in vivo.
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PMID:Phosphorylation of the nicotinic acetylcholine receptor by protein tyrosine kinases. 754 72


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