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)

The Golgi-localized, gamma-ear-containing, adenosine diphosphate ribosylation factor-binding proteins (GGAs) are multidomain proteins that bind mannose 6-phosphate receptors (MPRs) in the Golgi and have an essential role in lysosomal enzyme sorting. Here the GGAs and the coat protein adaptor protein-1 (AP-1) were shown to colocalize in clathrin-coated buds of the trans-Golgi networks of mouse L cells and human HeLa cells. Binding studies revealed a direct interaction between the hinge domains of the GGAs and the gamma-ear domain of AP-1. Further, AP-1 contained bound casein kinase-2 that phosphorylated GGA1 and GGA3, thereby causing autoinhibition. This could induce the directed transfer of the MPRs from GGAs to AP-1. MPRs that are defective in binding to GGAs are poorly incorporated into AP-1-containing clathrin-coated vesicles. Thus, the GGAs and AP-1 interact to package MPRs into AP-1-containing coated vesicles.
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PMID:Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network. 1221 46

Signaling from the transmembrane receptor Toll to Rel-related transcription factors regulates dorsoventral patterning of the Drosophila embryo, as well as larval and adult immunity. To identify additional pathway components, we have used double-stranded RNA interference to investigate Drosophila counterparts of genes that regulate the mammalian Rel family member NF-kappaB. Experiments in cultured cells reveal that the fly orthologue of the adaptor protein MyD88 is essential for signal transduction from Toll to a second adaptor protein, Tube. By using coimmunoprecipitation studies, we find a heterotrimeric association of the death domains of MyD88, Tube, and the protein kinase Pelle. Site-directed mutational analyses of interaction sites defined by crystallographic studies demonstrate that Tube recruits MyD88 and Pelle into the heterotrimer by two distinct binding surfaces on the Tube death domain. Furthermore, functional assays confirm that the formation of this heterotrimer is critical for signal transduction by the Toll pathway.
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PMID:A heterotrimeric death domain complex in Toll signaling. 1235 81

Reelin is a large secreted protein that controls cortical layering by signaling through the very low density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing tyrosine phosphorylation of the adaptor protein Disabled-1 (Dab1) and suppressing tau phosphorylation in vivo. Here we show that binding of Reelin to these receptors stimulates phosphatidylinositol 3-kinase, resulting in activation of protein kinase B and inhibition of glycogen synthase kinase 3beta. We present genetic evidence that this cascade is dependent on apolipoprotein E receptor 2, very low density lipoprotein receptor, and Dab1. Reelin-signaling components are enriched in axonal growth cones, where tyrosine phosphorylation of Dab1 is increased in response to Reelin. These findings suggest that Reelin-mediated phosphatidylinositol 3-kinase signaling in neuronal growth cones contributes to final neuron positioning in the mammalian brain by local modulation of protein kinase B and glycogen synthase kinase 3beta kinase activities.
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PMID:Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3beta. 1237 33

The production of red blood cells is tightly regulated by erythropoietin (Epo). The phosphoinositide 3-kinase (PI 3-kinase) pathway was previously shown to be activated in response to Epo. We studied the role of this pathway in the control of Epo-induced survival and proliferation of primary human erythroid progenitors. We show that phosphoinositide 3 (PI 3)-kinase associates with 4 tyrosine-phosphorylated proteins in primary human erythroid progenitors, namely insulin receptor substrate-2 (IRS2), Src homology 2 domain-containing inositol 5'-phosphatase (SHIP), Grb2-associated binder-1 (Gab1), and the Epo receptor (EpoR). Using different in vitro systems, we demonstrate that 3 alternative pathways independently lead to Epo-induced activation of PI 3-kinase and phosphorylation of its downstream effectors, Akt, FKHRL1, and P70S6 kinase: through direct association of PI 3-kinase with the last tyrosine residue (Tyr479) of the Epo receptor (EpoR), through recruitment and phosphorylation of Gab proteins via either Tyr343 or Tyr401 of the EpoR, or through phosphorylation of IRS2 adaptor protein. The mitogen-activated protein (MAP) kinase pathway was also activated by Epo in erythroid progenitors, but we found that this process is independent of PI 3-kinase activation. In erythroid progenitors, the functional role of PI 3-kinase was both to prevent apoptosis and to stimulate cell proliferation in response to Epo stimulation. Finally, our results show that PI 3-kinase-mediated proliferation of erythroid progenitors in response to Epo occurs mainly through modulation of the E3 ligase SCF(SKP2), which, in turn, down-regulates p27(Kip1) cyclin-dependent kinase (CDK) inhibitor via proteasome degradation.
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PMID:Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation. 1250 11

The biological functions of heterotrimeric G proteins and small GTPases are modulated by both extracellular stimuli and intracellular regulatory proteins. Using Saccharomyces cerevisiae two-hybrid screening, we identified tetratricopeptide repeat 1 (TPR1), a 292-amino-acid protein with three TPR motifs, as a Galpha16-binding protein. The interaction was confirmed both in vitro and in transfected mammalian cells, where TPR1 also binds to several other Galpha proteins. TPR1 was found to interact with Ha-Ras preferentially in its active form. Overexpression of TPR1 promotes accumulation of active Ras. TPR1 was found to compete with the Ras-binding domain (RBD) of Raf-1 for binding to the active Ras, suggesting that it may also compete with Ras GTPase-activating protein, thus contributing to the accumulation of GTP-bound Ras. Expression of Galpha16 strongly enhances the interaction between TPR1 and Ras. Removal of the TPR1 N-terminal 112 residues abolishes potentiation by Galpha16 while maintaining the interaction with Galpha16 and the ability to discriminate active Ras from wild-type Ras. We have also observed that LGN, a Galphai-interacting protein with seven TPR motifs, binds Ha-Ras. Thus, TPR1 is a novel adaptor protein for Ras and selected Galpha proteins that may be involved in protein-protein interaction relating to G-protein signaling.
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PMID:Identification of tetratricopeptide repeat 1 as an adaptor protein that interacts with heterotrimeric G proteins and the small GTPase Ras. 1274 87

The balance and cross-talk between natruretic and antinatruretic hormone receptors plays a critical role in the regulation of renal Na+ homeostasis, which is a major determinant of blood pressure. Dopamine and angiotensin II have antagonistic effects on renal Na+ and water excretion, which involves regulation of the Na+,K+-ATPase activity. Herein we demonstrate that angiotensin II (Ang II) stimulation of AT1 receptors in proximal tubule cells induces the recruitment of Na+,K+-ATPase molecules to the plasmalemma, in a process mediated by protein kinase Cbeta and interaction of the Na+,K+-ATPase with adaptor protein 1. Ang II stimulation led to phosphorylation of the alpha subunit Ser-11 and Ser-18 residues, and substitution of these amino acids with alanine residues completely abolished the Ang II-induced stimulation of Na+,K+-ATPase-mediated Rb+ transport. Thus, for Ang II-dependent stimulation of Na+,K+-ATPase activity, phosphorylation of these serine residues is essential and may constitute a triggering signal for recruitment of Na+,K+-ATPase molecules to the plasma membrane. When cells were treated simultaneously with saturating concentrations of dopamine and Ang II, either activation or inhibition of the Na+,K+-ATPase activity was produced dependent on the intracellular Na+ concentration, which was varied in a very narrow physiological range (9-19 mm). A small increase in intracellular Na+ concentrations induces the recruitment of D1 receptors to the plasma membrane and a reduction in plasma membrane AT1 receptors. Thus, one or more proteins may act as an intracellular Na+ concentration sensor and play a major regulatory role on the effect of hormones that regulate proximal tubule Na+ reabsorption.
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PMID:Intracellular Na+ regulates dopamine and angiotensin II receptors availability at the plasma membrane and their cellular responses in renal epithelia. 1275 48

Frizzled related proteins (Frps) are secreted proteins structurally similar to frizzled receptors; they bind Wnt via the cysteine-rich domain and antagonize the Wnt signaling pathway. In this study, we have investigated the mechanisms regulating the transcriptional regulation of rat Frp (rFrp) promoter. From previous findings, we know that the transcriptional activation domain of rFrp resides in the region -202 to -144 relative to the transcription start site, and that it is essential for efficient promoter activity. The study presented here was designed to identify trans-acting factors that bind to this critical domain of the rFrp promoter and to elucidate the pathway involved in the regulation of rFrp expression. Electrophoretic mobility shift assay (EMSA) demonstrated that specific DNA-protein binding activities fall into two adjacent core sequences with (CTTTGGGGG) at -197 to -189 and (AGATGATGTAA) at -151 to -141 of the rFrp promoter. Reporter assay showed that these core sequences are both required for the activation of rFrp promoter. Mutation within either one or both core sequence drastically reduced the promoter activity. Southwestern blotting showed that the estimated molecular mass of the distinct binding protein to the (AGATGATGTAA) domain is about 43 kDa. Further EMSA suggested CREB as the trans-acting factor in the DNA-protein complex, which was out competed by CREB consensus oligonucleotides and supershifted by anti-CREB antibody. Overexpression of PKA and CREB also transactivated rFrp promoter, and dominant-negative CREB inhibited the promoter activity in transient reporter assays. More importantly, CREB, phosphorylated CREB and the adaptor protein CBP were found binding to the endogenous rFrp promoter using chromatin immunoprecipitation assay. Collectively, our results demonstrate the induction of rFrp promoter activity by PKA and CREB in vitro, and the binding of CREB and CBP to the rFrp promoter core motif in vivo.
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PMID:Transcriptional regulation of the promoter of the rat frizzled related protein gene by CREB. 1281 63

Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK2) mediates multiple p38 MAPK-dependent inflammatory responses. To define the signal transduction pathways activated by MAPKAPK2, we identified potential MAPKAPK2 substrates by using a functional proteomic approach consisting of in vitro phosphorylation of neutrophil lysate by active recombinant MAPKAPK2, protein separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and phosphoprotein identification by peptide mass fingerprinting with matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and protein database analysis. One of the eight candidate MAPKAPK2 substrates identified was the adaptor protein, 14-3-3zeta. We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. The chemoattractant formyl-methionyl-leucyl-phenylalanine (fMLP) stimulated p38-MAPK-dependent phosphorylation of 14-3-3 proteins in human neutrophils. Mutation analysis showed that MAPKAPK2 phosphorylated 14-3-3zeta at Ser-58. Computational modeling and calculation of theoretical binding energies predicted that both phosphorylation at Ser-58 and mutation of Ser-58 to Asp (S58D) compromised the ability of 14-3-3zeta to dimerize. Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1. These data suggest that MAPKAPK2-mediated phosphorylation regulates 14-3-3zeta functions, and this MAPKAPK2 activity may represent a novel pathway mediating p38 MAPK-dependent inflammation.
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PMID:Proteomic identification of 14-3-3zeta as a mitogen-activated protein kinase-activated protein kinase 2 substrate: role in dimer formation and ligand binding. 1286 Oct 23

Reelin is a large secreted signaling protein that binds to two members of the low density lipoprotein receptor family, the apolipoprotein E receptor 2 and the very low density lipoprotein receptor, and regulates neuronal positioning during brain development. Reelin signaling requires activation of Src family kinases as well as tyrosine phosphorylation of the intracellular adaptor protein Disabled-1 (Dab1). This results in activation of phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt, and the inhibition of glycogen synthase kinase 3beta, a protein that is implicated in the regulation of axonal transport. Here we demonstrate that PI3K activation by Reelin requires Src family kinase activity and depends on the Reelin-triggered interaction of Dab1 with the PI3K regulatory subunit p85alpha. Because the Dab1 phosphotyrosine binding domain can interact simultaneously with membrane lipids and with the intracellular domains of apolipoprotein E receptor 2 and very low density lipoprotein receptor, Dab1 is preferentially recruited to the neuronal plasma membrane, where it is phosphorylated. Efficient Dab1 phosphorylation and activation of the Reelin signaling cascade is impaired by cholesterol depletion of the plasma membrane. Using a neuronal migration assay, we also show that PI3K signaling is required for the formation of a normal cortical plate, a step that is dependent upon Reelin signaling.
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PMID:Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination. 1288 64

Integrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from alpha4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient alpha4-mediated migration requires spatial control of alpha4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated alpha4 accumulated along the leading edge. Blocking alpha4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced alpha4-dependent migration and lamellipodial stability. alpha4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-alpha4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated alpha4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with alpha4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding.
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PMID:Spatial restriction of alpha4 integrin phosphorylation regulates lamellipodial stability and alpha4beta1-dependent cell migration. 1291 13


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