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)

Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial anomalies, webbed neck, sternal deformity, heart defects, and, in males, cryptorchidism. PTPN11 encodes SHP2, an important component of several signal transduction pathways that acts as a positive regulator of RAS-mitogen activated protein kinase signaling. Neurofibromatosis type 1 (NF1) is another autosomal dominant disorder characterized by hamartomas in multiple organs. The NF1 gene encodes a GAP-related protein, which acts as a negative regulator of the Ras-mediated signal transduction pathway. Clinical overlap between both syndromes, neurofibromatosis-Noonan syndrome (NFNS) is well known. We studied a female patient with typical findings of NFNS and found two mutations: a novel PTPN11 transversion, 1909A --> G, resulting in Gln510Arg, and an NF1 transversion, 2531A --> G, resulting in Leu844Arg. She inherited the PTPN11 mutation from her father and had a de novo NF1 mutation. This is the first report of molecular concurrence of both disorders in the same patient.
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PMID:Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. 1594 93

Protein kinases are the largest enzyme superfamily involved in cell signal transduction and represent therapeutic targets for a range of diseases. There have been intensive efforts from many labs to understand their catalytic mechanisms, discover inhibitors and discern their cellular functions. In this review, we will describe two approaches developed to analyze protein kinases: bisubstrate analog inhibition and phosphonate analog utilization. Both of these methods have been used in combination with the protein semisynthesis method expressed protein ligation to advance our understanding of kinase-substrate interactions and functional elucidation of phosphorylation. Previous work on the nature of the protein kinase mechanism suggests it follows a dissociative transition state. A bisubstrate analog was designed against the insulin receptor kinase to mimic the geometry of a dissociative transition state reaction coordinate distance. This bisubstrate compound proved to be a potent inhibitor against the insulin receptor kinase and occupied both peptide and nucleotide binding sites. Bisubstrate compounds with altered hydrogen bonding potential as well as varying spacers between the adenine and the peptide demonstrate the importance of the original design features. We have also shown that related bisubstrate analogs can be used to potently block serine/threonine kinases including protein kinase A. Since many protein kinases recognize folded protein substrates for efficient phosphorylation, it was advantageous to incorporate the peptide-ATP conjugates into protein structures. Using expressed protein ligation, a Src-ATP conjugate was produced and shown to be a high affinity ligand for the Csk tyrosine kinase. Nonhydrolyzable mimics of phosphoSer/phosphoTyr can be useful in examining the functionality of phosphorylation events. Using expressed protein ligation, we have employed phosphonomethylene phenylalanine and phosphonomethylene alanine to probe the phosphorylation of Tyr and Ser, respectively. These tools have permitted an analysis of the SH2-phosphatases (SHP1 and SHP2), revealing a novel intramolecular stimulation of catalytic activity mediated by the corresponding phosphorylation events. They have also been used to characterize the cellular regulation of the melatonin rhythm enzyme by phosphorylation.
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PMID:Protein kinase structure and function analysis with chemical tools. 1621 97

Fluid shear stress enhances NO production in endothelial cells by a mechanism involving the activation of the phosphatidylinositol 3-kinase and the phosphorylation of the endothelial NO synthase (eNOS). We investigated the role of the scaffolding protein Gab1 and the tyrosine phosphatase SHP2 in this signal transduction cascade in cultured and native endothelial cells. Fluid shear stress elicited the phosphorylation and activation of Akt and eNOS as well as the tyrosine phosphorylation of Gab1 and its association with the p85 subunit of phosphatidylinositol 3-kinase and SHP2. Overexpression of a Gab1 mutant lacking the pleckstrin homology domain abrogated the shear stress-induced phosphorylation of Akt but failed to affect the phosphorylation or activity of eNOS. The latter response, however, was sensitive to a protein kinase A (PKA) inhibitor. Mutation of Gab1 Tyr627 to phenylalanine (YF-Gab1) to prevent the binding of SHP2 completely prevented the shear stress-induced phosphorylation of eNOS, leaving the Akt response intact. A dominant-negative SHP2 mutant prevented the activation of PKA and phosphorylation of eNOS without affecting that of Akt. Moreover, shear stress elicited the formation of a signalosome complex including eNOS, Gab1, SHP2 and the catalytic subunit of PKA. In isolated murine carotid arteries, flow-induced vasodilatation was prevented by a PKA inhibitor as well as by overexpression of either the YF-Gab1 or the dominant-negative SHP2 mutant. Thus, the shear stress-induced activation of eNOS depends on Gab1 and SHP2, which, in turn, regulate the phosphorylation and activity of eNOS by a PKA-dependent but Akt-independent mechanism.
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PMID:Gab1, SHP2, and protein kinase A are crucial for the activation of the endothelial NO synthase by fluid shear stress. 1628 84

Fibroblast growth factor (FGF) signals are transduced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS-RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS approximately MAPK signaling cascade is implicated in cell growth and differentiation, the PI3K approximately AKT signaling cascade in cell survival and cell fate determination, and the PI3K approximately aPKC signaling cascade in cell polarity control. FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, while recombinant FGF2 protein and FGF4 expression vector are applicable for therapeutic angiogenesis. Helicobacter pylori, a causative pathogen for peptic ulcer diseases, chronic atrophic gastritis and gastric cancer, injects bacterial proteins into gastric epithelial cells by using Type IV secretion system, which leads to FGF signaling activation through FGF2 upregulation as well as CagA-dependent SHP2 activation. FGFR2 gene is preferentially amplified and overexpressed in diffuse-type gastric cancer. PD173074 is a small-molecule inhibitor for FGFR, while RO4396686 and SU6668 are small-molecule inhibitors for FGFR and other tyrosine kinases. Cocktail therapy using multiple protein kinase inhibitors could enhance the therapeutic effects for gastrointestinal cancer through the reduction of recurrence associated with somatic mutations of drug-target genes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of genes encoding FGF signaling molecules will be identified as novel risk factors of gastrointestinal cancer. Personalized prevention and personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of cancer patients.
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PMID:FGF signaling network in the gastrointestinal tract (review). 1677 96

Here, we demonstrate that elevation of intracellular cyclic AMP (cAMP) in vascular endothelial cells (ECs) by either a direct activator of adenylyl cyclase or endogenous cAMP-mobilizing G protein-coupled receptors inhibited the tyrosine phosphorylation of STAT proteins by an interleukin 6 (IL-6) receptor trans-signaling complex (soluble IL-6Ralpha/IL-6). This was associated with the induction of suppressor of cytokine signaling 3 (SOCS-3), a bona fide inhibitor in vivo of gp130, the signal-transducing component of the IL-6 receptor complex. Attenuation of SOCS-3 induction in either ECs or SOCS-3-null murine embryonic fibroblasts abolished the inhibitory effect of cAMP, whereas inhibition of SHP-2, another negative regulator of gp130, was without effect. Interestingly, the inhibition of STAT phosphorylation and SOCS-3 induction did not require cAMP-dependent protein kinase activity but could be recapitulated upon selective activation of the alternative cAMP sensor Epac, a guanine nucleotide exchange factor for Rap1. Consistent with this hypothesis, small interfering RNA-mediated knockdown of Epac1 was sufficient to attenuate both cAMP-mediated SOCS-3 induction and inhibition of STAT phosphorylation, suggesting that Epac activation is both necessary and sufficient to observe these effects. Together, these data argue for the existence of a novel cAMP/Epac/Rap1/SOCS-3 pathway for limiting IL-6 receptor signaling in ECs and illuminate a new mechanism by which cAMP may mediate its potent anti-inflammatory effects.
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PMID:Exchange protein activated by cyclic AMP (Epac)-mediated induction of suppressor of cytokine signaling 3 (SOCS-3) in vascular endothelial cells. 1691 20

Noonan syndrome is a relatively common, genetically heterogeneous Mendelian trait with a pleiomorphic phenotype. Prior to the period covered in this review, missense mutations in PTPN11 had been found to account for nearly 50% of Noonan syndrome cases. That gene encodes SHP-2, a protein tyrosine kinase that plays diverse roles in signal transduction including signaling via the RAS-mitogen activated protein kinase (MAPK) pathway. Noonan syndrome-associated PTPN11 mutations are gain-of-function, with most disrupting SHP-2's activation-inactivation mechanism. Here, we review recent information that has elucidated further the types and effects of PTPN11 defects in Noonan syndrome and compare them to the related, but specific, missense PTPN11 mutations causing other diseases including LEOPARD syndrome and leukemias. These new data derive from biochemical and cell biological studies as well as animal modeling with fruit flies and chick embryos. The discovery of KRAS missense mutation as a minor cause of Noonan syndrome and the pathogenetic mechanisms of those mutants is discussed. Finally, the elucidation of gene defects underlying two phenotypically related disorders, Costello and cardio-facio-cutaneous syndromes is also reviewed. As these genes also encode proteins relevant for RAS-MAPK signal transduction, all of the syndromes discussed in this article now can be understood to constitute a class of disorders caused by dysregulated RAS-MAPK signaling.
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PMID:Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. 1698 87

Regulation of growth factor dependent cell survival is crucial for development and disease progression. Here, we report a novel function of Src kinases as a negative regulator of platelet-derived growth factor (PDGF) dependent cell survival. We characterized a series of PDGF alpha receptor (PDGFRA) mutants, which lack the binding sites for Src, phosphatidylinositol 3'-kinase (PI3K), SHP-2 or phospholipase C-gamma. We found that PDGFRA-dependent cell survival was mainly mediated through activation of PI3K, and was negatively regulated by Src. Characterization of the downstream signaling events revealed that PI3K activates the protein kinase Akt, which in turn phosphorylates and thus inactivates proapoptotic Forkhead transcription factors. Src phosphorylates the ubiquitin-ligase c-Cbl, which is required for degradation of the activated receptor. Consequently, overexpression of c-Cbl prevented PDGFRA-mediated cell survival, whereas it did not affect this response, when Src was unable to associate with the receptor. This novel function of Src in antiapoptotic signaling introduces Src kinases as an interesting therapeutic target in apoptosis related diseases.
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PMID:PI3-kinase/Akt-dependent antiapoptotic signaling by the PDGF alpha receptor is negatively regulated by Src family kinases. 1714 Dec 22

Leukemia inhibitory factor (LIF), a cardiac hypertrophic cytokine, increases L-type Ca(2+) current (I(CaL)) via ERK-dependent and PKA-independent phosphorylation of serine 1829 in the Cav(1.2) subunit. The signaling cascade through gp130 is involved in this augmentation. However, there are two major cascades downstream of gp130, i.e. JAK/STAT3 and SHP2/ERK. In this study, we attempted to clarify which of these two cascades plays a more important role. Knock-in mouse line, in which the SHP2 signal was disrupted (gp130(F759/F759) group), and wild-type mice (WT group) were used. A whole-cell patch clamp experiment was performed, and intracellular Ca(2+) concentration ([Ca(2+)](i) transient) was monitored. The I(CaL) density and [Ca(2+)](i) transient were measured from the untreated cells and the cells treated with LIF or IL-6 and soluble IL-6 receptor (IL-6+sIL-6r). Action potential duration (APD) was also recorded from the ventricle of each mouse, with or without LIF. Both LIF and IL-6+sIL-6r increased I(CaL) density significantly in WT (+27.0%, n=16 p<0.05, and +32.2%, n=15, p<0.05, respectively), but not in gp130(F759/F759) (+9.4%, n=16, NS, and -6.1%, n=13, NS, respectively). Administration of LIF and IL-6+sIL-6r increased [Ca(2+)](i) transient significantly in WT (+18.8%, n=13, p<0.05, and +32.0%, n=21, p<0.05, respectively), but not in gp130(F759/F759) (-3.8%, n=7, NS, and -6.4%, n=10, NS, respectively). LIF prolonged APD(80) significantly in WT (10.5+/-4.3%, n=12, p<0.05), but not in gp130(F759/F759) (-2.1+/-11.2%, n=7, NS). SHP2-mediated signaling cascade is essential for the LIF and IL-6+sIL-6r-dependent increase in I(CaL), [Ca(2+)](i) transient and APD.
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PMID:SHP2-mediated signaling cascade through gp130 is essential for LIF-dependent I CaL, [Ca2+]i transient, and APD increase in cardiomyocytes. 1796 93

The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html).
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PMID:The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. 1847 Sep 43

The effect of early intervention with a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist on skeletal muscle GLUT4 translocation and insulin signaling was examined in intrauterine (IUGR) and postnatal (PNGR) growth-restricted pregestational female rat offspring. Rosiglitazone [11 mumol/day provided from postnatal day (PN)21 to PN60] improved skeletal muscle insulin sensitivity and GLUT4 translocation in prenatal nutrient restriction [50% calories from embryonic day (e)11 to e21; IUGR] with (IUGR+PNGR) and without (IUGR) postnatal nutrient restriction (50% calories from PN1 to PN21; PNGR) similar to that of control (ad libitum feeds throughout; Con) (n = 6 each). This was accomplished by diminished basal and improved insulin-responsive GLUT4 association with the plasma membrane in IUGR, IUGR+PNGR, and PNGR mimicking that in Con (P < 0.005). While no change in p85-phosphatidylinositol 3-kinase (PI3-K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed, a decrease in protein tyrosine phosphatase 1B (PTP1B; P < 0.0002) and SH2-containing protein tyrosine phosphatase 2 (SHP2; P < 0.05) contributing to the rosiglitazone-induced insulin sensitivity was seen only in IUGR+PNGR. In contrast, an increase in phosphorylated 5'-adenosine monophosphate kinase (pAMPK; P < 0.04) and insulin responsiveness of phosphorylated phosphoinositide-dependent protein kinase-1 (pPDK1; P < 0.05), pAkt (P < 0.01), and particularly pPKCzeta (P < 0.0001) and its corresponding enzyme activity (P < 0.005) were observed in all four experimental groups. We conclude that early introduction of PPARgamma agonist improved skeletal muscle activation of AMPK and insulin signaling, resulting in insulin-independent AMPK and insulin-responsive GLUT4 association with plasma membranes in IUGR, IUGR+PNGR, and PNGR adult offspring, similar to that of Con. These findings support a role for insulin sensitizers in preventing the subsequent development of gestational or type 2 diabetes mellitus in intrauterine and postnatal growth-restricted offspring.
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PMID:Peroxisome proliferator-activated receptor-gamma agonist improves skeletal muscle insulin signaling in the pregestational intrauterine growth-restricted rat offspring. 1949


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