Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “TYROSINE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 721 records · Page 40Linked to original sources
PubMed1997

Interleukin-3 induces association of the protein-tyrosine phosphatase SHP2 and phosphatidylinositol 3-kinase with a 100-kDa tyrosine-phosphorylated protein in hemopoietic cells.

We have observed previously the co-immunoprecipitation of the p85 subunit of phosphatidylinositol-3 kinase (PI3K) and SHP2 in murine lymphohemopoietic cells after stimulation with interleukin-3. We have investigated this interaction in more detail and now report the identification of a potentially novel 100-kDa protein (termed p100), which is inducibly phosphorylated on tyrosine after interleukin-3 treatment and which co-immunoprecipitates with both p85 PI3K and SHP2. The Src homology region 2 domains of both p85 and SHP2 appear to mediate their interactions with p100. Sequential precipitation analyses suggest that these interactions are direct and do not involve Grb2, and that the same p100 protein, or a portion of it, interacts with both p85 and SHP2, implying that p100 may serve to link these two proteins. Far Western blotting with both full-length p85 and isolated p85 Src homology region 2 domains supports this view. Interestingly, p100 also appears to be a substrate for the SHP2 phosphatase activity. In addition, p100 is precipitated by Grb2-glutathione S-transferase fusion proteins, an interaction largely mediated by the Grb2 SH3 domains. p100 appears to be distinct from JAK2, Vav, STAT5, and c-Cbl. Although largely cytosolic, p100 can be detected associated with SHP2 and PI3K in crude membrane fractions after interleukin-3 stimulation. We propose that p100 plays a role as an adaptor molecule, linking PI3K and SHP2 in IL-3 signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2000

GTK, a Src-related tyrosine kinase, induces nerve growth factor-independent neurite outgrowth in PC12 cells through activation of the Rap1 pathway. Relationship to Shb tyrosine phosphorylation and elevated levels of focal adhesion kinase.

The rat pheochromocytoma cell line PC12 is extensively used as a model for studies of neuronal cell differentiation. These cells develop a sympathetic neuron-like phenotype when cultured in the presence of nerve growth factor. The present study was performed in order to assess the role of mouse GTK (previously named BSK/IYK), a cytoplasmic tyrosine kinase belonging to the Src family, for neurite outgrowth in PC12 cells. We report that PC12 cells stably overexpressing GTK exhibit a larger fraction of cells with neurites as compared with control cells, and this response is not accompanied by an increased ERK activity. Treatment of the cells with the MEK inhibitor PD98059 did not reduce the GTK-dependent increased in neurite outgrowth. GTK expression induces a nerve growth factor-independent Rap1 activation, probably through altered CrkII signaling. We observe increased CrkII complex formation with p130(Cas), focal adhesion kinase (FAK), and Shb in PC12-GTK cells. The expression of GTK also correlates with a markedly increased content of FAK, phosphorylation of the adaptor protein Shb, and an association between these two proteins. Transient transfection of GTK-overexpressing cells with RalGDS-RBD or Rap1GAP, inhibitors of the Rap1 pathway, reduces the GTK-dependent neurite outgrowth. These data suggest that GTK participates in a signaling pathway, perhaps involving Shb, FAK and Rap1, that induces neurite outgrowth in PC12 cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Tyrosine kinase signalling in breast cancer: tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer.

The ability of growth factors and their cognate receptors to induce mammary epithelial proliferation and differentiation is dependent on their ability to activate a number of specific signal transduction pathways. Aberrant expression of specific receptor tyrosine kinases (RTKs) has been implicated in the genesis of a significant proportion of sporadic human breast cancers. Indeed, mammary epithelial expression of activated RTKs such as ErbB2/neu in transgenic mice has resulted in the efficient induction of metastatic mammary tumours. Although it is clear from these studies that activation these growth factor receptor signalling cascades are directly involved in mammary tumour progression, the precise interaction of each of these signalling pathways in mammary tumourigenesis and metastasis remains to be elucidated. The present review focuses on the role of several specific signalling pathways that have been implicated as important components in RTK-mediated signal transduction. In particular, it focuses on two well characterized transgenic breast cancer models that carry the polyomavirus middle T(PyV mT) and neu oncogenes.

Animals↗
PubMed1999

Molecular evolution of peptide tyrosine--tyrosine: primary structure of PYY from the lampreys Geotria australis and Lampetra fluviatilis, bichir, python and desert tortoise.

Peptide tyrosine-tyrosine (PYY) has been isolated from the intestines of two species of reptile, the desert tortoise Gopherus agassizii (Testudines) and the Burmese python Python molurus (Squamata), from the primitive Actinopterygian fish, the bichir Polypterus senegalis (Polypteriformes) and from two agnathans, the Southern-hemisphere lamprey Geotria australis (Geotriidae) and the holarctic lamprey Lampetra fluviatilis (Petromyzontidae). The primary structure of bichir PYY is identical to the proposed ancestral sequence of gnathostome PYY (YPPKPENPGE10/DAPPEELAKY20/YSALR HYINL30/ITRQRY). Tortoise and python PYY differ by six and seven residues, respectively, from the ancestral sequence consistent with the traditional view that the Testudines represent an earlier divergence from the primitive reptilian stock than the Squamates. The current views of agnathan phylogeny favor the hypothesis that the Southern-hemisphere lampreys and the holarctic lampreys arose from a common ancestral stock but their divergence is of a relatively ancient (pre-Tertiary) origin. The Geotria PYY-related peptide shows only two amino acid substitutions (Pro10-->Gln and Leu22-->Ser) compared with PYY from the holarctic lamprey Petromyzon marinus. This result was unexpected as Petromyzon PYY differs from Lampetra PYY deduced from the nucleotide sequence of a cDNA (Söderberg et al. J. Neurosci. Res. 1994;37:633-640) by 10 residues. However, a re-examination of an extract of Lampetra intestine revealed the presence of a PYY that differed in primary structure from Petromyzon PYY by only one amino acid residue (Pro10-->Ser). This result suggests that the structure of PYY has been strongly conserved during the evolution of Agnatha and that at least two genes encoding PYY-related peptides are expressed in Lampetra tissues.

Amino Acid Sequence↗
PubMed2001

Anomalous rates of evolution of pancreatic polypeptide and peptide tyrosine-tyrosine (PYY) in a tetraploid frog, Xenopus laevis (Anura:Pipidae).

The South African clawed frog Xenopus laevis is believed to have arisen as a result of a tetraploidization event occurring approximately 30 million years ago. Two molecular forms of pancreatic polypeptide (PP) have been isolated from an extract of the pancreas of this species and two molecular forms of peptide tyrosine-tyrosine (PYY) from the intestine. Despite the fact that the amino acid sequence of PP has, in general, been very poorly conserved during the evolution of tetrapods (only Pro(5), Pro(8), Gly(9), Ala(12), Tyr(27), Arg(33) and Arg(35) are invariant among species studied so far), the two Xenopus PPs differ by only a single amino acid substition (Asp(22)-->Glu). In contrast the two molecular forms of PYY differ by six amino acid substitutions (Glu(15)-->Gln, Thr(18)-->Ala, Leu(21)-->Met, Ile(22)-->Thr, Ile(28)-->Val, Val(31)-->Ile). The data imply that strong evolutionary pressure is acting to conserve the functional domain in both genes encoding PP and so suggest that PP may have an important physiological role in amphibians (although the nature of this role has yet to be determined). The more rapid mutation of the functional domain in the genes encoding PYY, a peptide whose amino acid sequence has been quite well conserved in tetrapods and whose physiological significance is well established, suggests that one of the PYY genes may be evolving towards a new function or towards becoming a pseudogene.

Amino Acid Sequence↗
PubMed2006

The role of oxyntomodulin and peptide tyrosine-tyrosine (PYY) in appetite control.

Oxyntomodulin and peptide tyrosine-tyrosine (PYY) are released from intestinal enteroendocrine cells in response to a meal. These circulating hormones are considered to be satiety signals, as they have been found to decrease food intake, body weight and adiposity in rodents. Their effect on energy homeostasis is mediated by the hypothalamus and brainstem, and several studies have demonstrated alterations in neuropeptide signaling within the arcuate nucleus. The weight loss that has been observed in animal models after repeated administration of oxyntomodulin and PYY has led to interest in developing these peptides as antiobesity therapies in humans. Indeed, preliminary studies have found that oxyntomodulin or PYY administration reduces food intake and body weight effectively in overweight human volunteers. This research suggests that modulation of these gut hormones could prove to be effective long-term therapies in the quest to combat the obesity epidemic.

Animals↗
PubMed1992

Expression of ileal glucagon and peptide tyrosine-tyrosine genes. Response to inhibition of polyamine synthesis in the presence of massive small-bowel resection.

Massive small-bowel resection results in a marked adaptive response in the residual terminal ileum. Increased polyamine synthesis is a necessary component of this response. The ileal L-cell-derived peptides enteroglucagon and peptide tyrosine tyrosine (PYY) have been implicated as humoral mediators of this response. We have previously reported a rapid and sustained increase in glucagon mRNA concentrations after massive small-bowel resection. In this study using an inhibitor of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase, we have demonstrated that the response of the glucagon and PYY genes to massive small-bowel resection is dependent on polyamine biosynthesis. In addition, we have examined the response of both the ornithine decarboxylase and c-jun genes in this model of intestinal adaptation.

Animals↗
PubMed1989

Meal-induced peptide tyrosine tyrosine inhibition of pancreatic secretion in the rat.

In the present studies we examined the distribution, release, and biological actions of peptide tyrosine tyrosine (PYY) in the rat. The concentration and distribution of PYY was highest in the ileum and colon as determined by both radioimmunoassay of rat tissue extracts and immunocytochemistry. An ultrastructural comparison of rat and dog colonic PYY cells revealed a bipolar distribution of peptide-containing secretory granules in both species. Serum PYY and pancreatic exocrine secretory responses were monitored after presentation of a meal to meal-trained rats (n = 12). A significant increase in PYY concentrations was not observed until 120 min after meal presentation, a delayed response similar to that previously observed in the dog. PYY responses were also observed in rats after perfusion of the intestine at the level of the duodenum and ileum with an 80 mOsm micellar solution of sodium oleate. Duodenal instillations of the fatty acids resulted in a maximum PYY response after 120 min, whereas rats subject to ileal perfusion of fat exhibited maximum PYY release within the first hour. In other experiments, infusion of exogenous PYY at 100 pmol.kg-1.h-1, which reproduced plasma PYY levels observed after a meal and perfusion of the gut with fat, significantly inhibited CCK-stimulated bile pancreatic volume (P less than 0.02), protein (P less than 0.01), and amylase (P less than 0.01) output. These studies demonstrate a bipolar distribution of PYY-containing secretory granules in cells of the jejunal, ileal, and colonic mucosa, and show that PYY is released in response to a meal in amounts sufficient to inhibit cholecystokinin-stimulated pancreatic secretion. Evidence is presented that PYY may mediate the delayed inhibition of pancreatic secretion that is observed in the rat after ingestion of a meal.

Animals↗
PubMed1991

Peptide tyrosine tyrosine-positive ovarian carcinoid tumor arising from a dermoid cyst.

A case of ovarian carcinoid tumor of the trabecular type is presented. The small carcinoid tumor was found incidentally in a resected dermoid cyst. Histologically, the tumor was surrounded by a smooth muscle layer with focal stromal invasion. Non-carcinoid papillary mucosa and a few small glands, simulating the mucosa of the fallopian tube and remnant müllerian glands, respectively, were also present adjacent to the carcinoid tumor and enclosed by the same smooth muscle layer. The tumor cells revealed argyrophilia, and were positive for peptide tyrosine tyrosine (PYY) in the cytoplasm and for CEA in part of the luminal surface. This case was considered to be a rare ovarian carcinoid tumor arising from a dermoid cyst, without association of struma ovarii. PYY may be a potential marker for determining the histogenesis of ovarian carcinoid tumors.

Adult↗
PubMed1993

In vitro tyrosine phosphorylation of PLC-gamma 1 and PLC-gamma 2 by src-family protein tyrosine kinases.

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. Comparison of the in vitro phosphorylation rates revealed no distinct specificity between PLC-gamma 1 and PLC-gamma 2, or between the five PTKs.

Humans↗
PubMedDate not supplied

The enhancement by pervanadate of tyrosine phosphorylation on prostatic proteins occurs through the inhibition of membrane-associated tyrosine phosphatases.

The relapse of prostate cancer during endocrine therapies is attributed to the proliferation of growth factor (GF)-dependent epithelial cells. Such cells are present but in a quiescent state in the normal adult human and dog (experimental model) prostates. GF-signaling pathways involve the activation of protein tyrosine kinases (PTK) whose action is also modulated by phosphotyrosine protein phosphatases (PTPs). To that effect, we have previously reported that dividing canine prostatic epithelial cells exhibited high levels of phosphotyrosyl-(pY)-proteins which were greatly enhanced when incubated in the presence of vanadate. The aim of this study, performed with pervanadate (pV), was to determine whether pV acts either directly by stimulating prostatic PTKs or indirectly by inhibiting PTPs. Upon fractionation, most of the PTK activity was found in membranes of dividing cells and pV selectively increased its activity. This was due to an inhibition of intrinsic PTPs, as demonstrated by dephosphorylation of endogenous pY-proteins which was abolished by pV. This activity was very sensitive to pV (IC50: 150 nM) and was due to non-secreted forms of prostatic acid phosphatase (PAP), a pV inhibited-enzyme, as well as to PTP-1 B, as demonstrated by gel filtration, isoelectric focusing and probing with antibodies. These enzymes were also detected in membranes from human hyperplastic/neoplastic prostates but only PTP-1 B was present in those of prostatic carcinoma PC3 cells. These PTPs, bound to membranes of dividing cells (normal vs neoplastic) where activated PTKs are also located, may be of importance in the development and progression of prostatic proliferative diseases.

Animals↗
PubMed2005

Transfection of tyrosine kinase deleted FGF receptor-1 into rat brain substantia nigra reduces the number of tyrosine hydroxylase expressing neurons and decreases concentration levels of striatal dopamine.

The effects of HSV-1 amplicon and polyethyleneimine (PEI)-mediated transfection of dominant negative FGF receptor-1 mutant FGFR1(TK-) into the rat brain substantia nigra (SN) were examined in vivo to model the reduced FGF signaling documented to occur in Parkinson's disease. The number of SN neurons that expressed tyrosine hydroxylase (TH) was significantly reduced following HSV-1 FGFR1(TK-) intranigral delivery and similar changes were observed after PEI-mediated FGFR1(TK-) transfections. Further, we also observed a significantly lower striatal dopamine content following the PEI transfection of FGFR1(TK-). Thus, we conclude that reduced FGF signaling in the SN of Parkinsonian patients could play a role in the impaired dopaminergic transmission associated with the degenerative disease.

Animals↗
PubMed1998

Tyrosine phosphorylation of the TATA element modulatory factor by the FER nuclear tyrosine kinases.

The FER locus in the mouse encodes two tyrosine kinases, p94fer and p51ferT. While p94fer accumulates in the cytoplasm and nucleus of most mammalian cells the expression of p51ferT is restricted to the nucleus of meiotic primary spermatocytes. The cellular function of the FER kinases is not understood, nor has a substrate for these enzymes been characterized. To identify putative substrates of p94fer and p51ferT, the two enzymes were used as 'baits' in the yeast two-hybrid screening system. cDNAs encoding the mouse TATA element modulatory factor (TMF) were repeatedly isolated in this assay. TMF was previously shown to bind the TATA element in RNA polymerase II promoters and impaired their functioning in a cell free transcription system. Both p94fer and p51ferT phosphorylated the TMF protein in in vitro and in vivo kinase assays. Sequential deletions showed that the carboxy-terminal region of TMF was essential for phosphorylation. In situ hybridization analysis revealed the preferential accumulation of TMF transcripts in meiotic spermatogenic and oogenic cells. p94fer and p51ferT may thus modulate the suppressive activity of TMF during cellular growth and in defined differentiation processes.

Animals↗
PubMed1998

The effect of tyrosine-deficient total parenteral nutrition on the synthesis of dihydroxyphenylalanine in neural tissue and the activities of tyrosine and branched-chain aminotransferases.

The poor solubility of tyrosine (Tyr) limits the amount of this amino acid in total parenteral nutrition (TPN). In rats maintained on a standard pediatric TPN mixture, plasma and brain concentrations of Tyr are reduced to about 25% of the levels in chow-fed controls. To determine whether these low concentrations of Tyr affect the synthesis of catecholamines in neural tissue, the rate-limiting step (conversion of Tyr to dihydroxyphenylalanine [DOPA]) is studied by administering NSD-1015 to block the pyridoxal phosphate (PLP)-dependent decarboxylation of DOPA. However, in TPN rats, plasma concentrations of Tyr are increased by drug treatment. Because brain Tyr is also increased, these and other experiments using NSD-1015 clearly overestimate the rate of DOPA synthesis for drug-free rats on TPN. Nevertheless, in TPN rats, there is less DOPA in the brain in one experiment and less DOPA in the olfactory bulbs in another, versus control rats. Further examination of the metabolic effects of NSD-1015 reveals that the drug also elevates the concentration of branched-chain amino acids (BCAAs) in the plasma of TPN rats. These findings result from inhibition by NSD-1015 of the PLP-dependent aminotransferases that initiate catabolism of Tyr in the liver and BCAAs in the muscle. Despite the pronounced reduction in plasma Tyr, TPN rats showed a marked increase in the activity of hepatic Tyr aminotransferase compared with chow-fed controls. Conversely, although TPN elevates BCAA concentrations in plasma, the activity of branched-chain aminotransferase (BCAT) in the heart muscle of TPN rats is not different from control values. Different values but the same relationships are seen in drug-free rats.

Amino Acids, Branched-Chain↗
PubMed2003

Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction.

In addition to protein phosphorylation, redox-dependent post-translational modification of proteins is emerging as a key signaling system that has been conserved throughout evolution and that influences many aspects of cellular homeostasis. Both systems exemplify dynamic regulation of protein function by reversible modification, which, in turn, regulates many cellular processes such as cell proliferation, differentiation and apoptosis. In this article we focus on the interplay between phosphorylation- and redox-dependent signaling at the level of phosphotyrosine phosphatase-mediated regulation of receptor tyrosine kinases (RTKs). We propose that signal transduction by oxygen species through reversible phosphotyrosine phosphatase inhibition, represents a widespread and conserved component of the biochemical machinery that is triggered by RTKs.

Animals↗
PubMed1998

Synthesis and tyrosine kinase inhibitory activity of a series of 2-amino-8H-pyrido[2,3-d]pyrimidines: identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors.

Screening of a compound library led to the identification of 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidine (1) as a inhibitor of the platelet-derived growth factor receptor (PDGFr), fibroblast growth factor receptor (FGFr), and c-src tyrosine kinases (TKs). Replacement of the primary amino group at C-2 of 1 with a 4-(N,N-diethylaminoethoxy)phenylamino group yielded 2a, which had greatly increased activity against all three TKs. In the present work, variation of the aromatic group at C-6 and of the alkyl group at N-8 of the pyrido[2,3-d]pyrimidine core provided several analogues that retained potency, including derivatives that were biased toward inhibition of the TK activity of PDGFr. Analogues of 2a with a 3-thiophene or an unsubstituted phenyl group at C-6 were the most potent inhibitors. Compound 54, which had IC50 values of 31, 88, and 31 nM against PDGFr, FGFr, and c-src TK activity, respectively, was active in a variety of PDGF-dependent cellular assays and blocked the in vivo growth of three PDGF-dependent tumor lines.

3T3 Cells↗
PubMed1998

Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions.

HEK2 belongs to the family of EPH-related receptor tyrosine kinases (RTK) which are involved in axonal pathfinding and the formation of the embryonic body plan. The knowledge about intracellular pathways of signal transduction mediated by EPH-related receptors is still limited. Many of the known key players of cellular signalling contain Src homology 2 (SH2) domains, which recognize phosphotyrosine motifs in RTKs. Thus, we examined the interactions of various SH2-containing molecules like PLC-gamma1, rasGAP, p85 subunit of PI3-kinase, Src, Fyn, Crk, Nck, Grb2 and Shc with HEK2 using in vitro binding assays, immunoprecipitations and yeast Two-Hybrid assays. We found that rasGAP, Crk and Fyn bind in a SH2-dependent manner to autophosphorylated HEK2. rasGAP, which contains two SH2- and one SH3-domain, was shown to associate with its N-terminal SH2-domain to HEK2. Furthermore, we demonstrated that a single amino acid substitution (Y614F) clearly reduces the phosphotyrosine content of HEK2 and abrogates its ability to bind rasGAP, Crk and Fyn indicating that this residue functions as major phosphorylation and multi-docking site. The conservation of this predicted binding site among various EPH-related RTKs provides evidence that Fyn, Crk and rasGAP are key players in signal transduction of at least a subset of these receptors.

Binding Sites↗
PubMed2002

Threonine-124 and phenylalanine-448 in Citrobacter freundii tyrosine phenol-lyase are necessary for activity with L-tyrosine.

Thr-124 and Phe-448 are located in the active site of Citrobacter freundii tyrosine phenol-lyase (TPL) near the phenol ring of a bound substrate analogue, 3-(4'-hydroxyphenyl)propionic acid [Sundararaju, Antson, Phillips, Demidkina, Barbolina, Gollnick, Dodson and Wilson (1997) Biochemistry 36, 6502-6510]. Thr-124 is replaced by Asp and Phe-448 is replaced by His in the crystal structure of a structurally similar enzyme, Proteus vulgaris tryptophan indole-lyase, which has 50% identical residues. Hence, Thr-124 and Phe-448 in TPL were mutated to Ala or Asp, and His, respectively, in order to probe the role of these residues in the reaction specificity for L-Tyr. These mutant enzymes have little or no beta-elimination activity with L-Tyr or 3-fluoro-L-Tyr as a substrate, but retain significant elimination activity with S-(o-nitrophenyl)-L-cysteine, S-alkyl-L-cysteines and beta-chloroalanine. Furthermore, the binding of L-Tyr and other non-substrate amino acids is not significantly affected by the mutations. The mutant TPLs form intermediates in rapid-scanning stopped-flow experiments with L-Phe, L-Tyr and L-Trp, similar to those seen with wild-type TPL. These results demonstrate that Thr-124 and Phe-448 are necessary for the reaction specificity of TPL for L-Tyr, and probably play a role in the elimination stage of the reaction mechanism. Thr-124 is within hydrogen-bonding distance of the phenolic group of the bound substrate, and may help to orientate the ring for beta-elimination to occur. Phe-448 may be important to allow the formation of the closed conformation during the reaction.

Amino Acid Sequence↗