Nanopublications LDF server

Matches in Nanopublications for { ?s <http://www.w3.org/ns/prov#value> ?o ?g. }

• _2 value "the Toll-like receptor (TLR) pattern recognition receptors, are essential for the innate immune response to components of Gram-negative and Gram-positive bacteria, mycobacteria, spirochetes and yeast. We now find that these receptors function in an antiviral response as well. The innate immune response to the fusion protein of an important respiratory pathogen of humans, respiratory syncytial virus (RSV), was mediated by TLR4 and CD14. RSV persisted longer in the lungs of infected TLR4-deficient mice compared to normal mice." provenance.
• _4 value "Whereas cdk4/cdk6 inhibition and Rb dephosphorylation are expected on p16Ink4a expression, we have also observed indirect cdk2 inhibition." provenance.
• _4 value "Phosphorylation of IRS-1 by PKCzeta specifically impairs insulin-stimulated tyrosine phosphorylation at residues 612 and 632. This phosphorylation somehow interferes the ability to activate PI3K. Thus PKC-zeta may participate in negative feedback." provenance.
• _4 value "Western blot analysis confirmed the induction of MMP-2, MMP-12, MMP-13, and MMP-14 (Figure 7a, and data not shown) and immunohistochemistry demonstrated that MMP-12 was seen predominantly in macrophages, and MMP-9 was seen in parenchymal locations in epithelial cells and interstitial fibroblast-like cells (Figure 7, b–f, and data not shown)." provenance.
• _4 value "Western blot analysis confirmed the induction of MMP-2, MMP-12, MMP-13, and MMP-14 (Figure 7a, and data not shown) and immunohistochemistry demonstrated that MMP-12 was seen predominantly in macrophages, and MMP-9 was seen in parenchymal locations in epithelial cells and interstitial fibroblast-like cells (Figure 7, b–f, and data not shown)." provenance.
• _3 value "After beta-adrenergic stimulation (iso 3 h) but not after control perfusion (control 3 h) a roughly threefold increase in B-CK mRNA levels and a decrease in M-CK mRNA levels by 18% was found." provenance.
• _3 value "After beta-adrenergic stimulation (iso 3 h) but not after control perfusion (control 3 h) a roughly threefold increase in B-CK mRNA levels and a decrease in M-CK mRNA levels by 18% was found." provenance.
• _5 value "Stimulation of cartilage explants with IL-6 and/or sIL-6R potentiated aggrecan catabolism and release above that seen in the presence of IL-1alpha or TNF-alpha alone. This catabolism was associated with aggrecanase (but not MMP) activity, with correlative mRNA expression for aggrecanase-2." provenance.
• _4 value "Incubation of COS-1 cells with 8-bromo-cAMP resulted in activation of the MAPK pathway, as determined by Western blotting with antibodies to the phosphorylated (active) form of Erk-1/2, suggesting an indirect pathway to SRC-1 phosphorylation. Elevation of intracellular cyclic AMP (cAMP), a common second messenger for a number of hormones and a direct activator of protein kinase A (PKA), can induce a ligand-independent activation of chicken PR (cPR) (22), AR (44), and the ER (8), as well as enhance steroid-dependent activation of a broader range of receptors, including PR (13, 35), ER (8), GR (45), AR (19, 30), and the mineralocorticoid receptor (41)." provenance.
• _3 value "To determine if other receptor-associated cofactors were targets of cAMP-dependent signaling pathways, we examined the phosphorylation of steroid receptor coactivator 1 (SRC-1). We detected a 1.8-fold increase in SRC-1 phosphorylation in transfected COS-1 cells incubated with 8-bromo-cAMP. Phosphorylation was increased on two mitogen-activated protein kinase (MAPK) sites, threonine 1179 and serine 1185." provenance.
• _5 value "To determine if other receptor-associated cofactors were targets of cAMP-dependent signaling pathways, we examined the phosphorylation of steroid receptor coactivator 1 (SRC-1). We detected a 1.8-fold increase in SRC-1 phosphorylation in transfected COS-1 cells incubated with 8-bromo-cAMP. Phosphorylation was increased on two mitogen-activated protein kinase (MAPK) sites, threonine 1179 and serine 1185." provenance.
• _5 value "To determine if other receptor-associated cofactors were targets of cAMP-dependent signaling pathways, we examined the phosphorylation of steroid receptor coactivator 1 (SRC-1). We detected a 1.8-fold increase in SRC-1 phosphorylation in transfected COS-1 cells incubated with 8-bromo-cAMP. Phosphorylation was increased on two mitogen-activated protein kinase (MAPK) sites, threonine 1179 and serine 1185." provenance.
• _4 value "Pulldown experiments employing the GST-Rap1 binding domain of RalGDS as a probe for the active form of Rap1 ( 12 ) showed that stimulation of CD45 RO + BW cells with MAb 5A induces less accumulation of Rap1-GTP than does similar treatment with MAb 3D3 (Fig. 5 A, left)." provenance.
• _6 value "Here we show that Forkhead transcription factors FKHRL1 and FKHR, substrates of the Akt kinase, are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells. Restoration of PTEN function restores FKHR to the nucleus and restores transcriptional activation." provenance.
• _3 value "Although Tyr-239/240 and Tyr-317 residues are the possible candidates of Shc phosphorylation sites, insulin predominantly phosphorylates the Shc Tyr-317 residue." provenance.
• _3 value "Furthermore, we demonstrate that binding of Grb7 to tyrosine 14-phosphorylated caveolin-1 functionally augments anchorage-independent growth and epidermal growth factor (EGF)-stimulated cell migration." provenance.
• _6 value "High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells [vascular SMCs and ECs]" provenance.
• _4 value "200 U/ml of IL-1beta increases the expression of vimentin in GL15 apoptotic cells." provenance.
• _7 value "Execution of the muscle differentiation program requires release of MEF2 from repression by HDACs, which are expressed constitutively in myoblasts and myotubes. Calcium/calmodulin-dependent protein kinase (CaMK) signalling, which stimulates myogenesis and prevents formation of MEF2-HDAC complexes, also induces nuclear export of HDAC4 and HDAC5 by phosphorylation of these transcriptional repressors." provenance.
• _6 value "Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors associate with myogenic basic helix-loop-helix transcription factors such as MyoD to activate skeletal myogenesis." provenance.
• _6 value "Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors associate with myogenic basic helix-loop-helix transcription factors such as MyoD to activate skeletal myogenesis." provenance.
• _5 value "Transient expression of Asp1 in APP-expressing cells results in an increase in the level of beta-secretase-derived soluble APP and the corresponding carboxy-terminal fragment." provenance.
• _6 value "Modified assertion" provenance.
• _3 value "table 1 - genes induced by E2 in breast cancer cells" provenance.
• _5 value "Using transient transfection and EMSA, we demonstrate that IL-4-activated STAT-6 binds to two different SBEs in the human CD40 promoter to inhibit STAT-1 -mediated CD40 promoter activity." provenance.
• _3 value "One such risk factor is oxLDL, which exert pro-apoptotic effects on a variety of cell lineages, including endothelial cells and VSMCs, both in cultured cells and in arteries [19–26]. Increased formation of oxygen radicals (and other radical species) facilitates LDL oxidation and influences oxidation-sensitive mechanisms [15]." provenance.
• _3 value "Not surprisingly, high concentrations of exogenous reactive oxygen species (ROS), generated by enzymatic reactions or by radiation, also stimulate the apoptosis of endothelial cells in vitro [29–31]." provenance.
• _3 value "For instance, during 7-ketocholesterol-induced apoptosis of U937 cells, the cellular antioxidant content falls rapidly [64], but administration of two potent antioxidants, the aminothiols glutathione and N-acetylcysteine, can protect themonocytic cells from 7-ketocholesterol-induced apoptotic cell death [64]." provenance.
• _5 value "In addition, another oxygen-radical scavenger enzyme, catalase, can prevent VSMC apoptosis triggered by hydrogen peroxide [27,65]." provenance.
• _5 value "Akt Ser473 was strongly induced in wild-type cells by different growth factors such as the platelet-derived growth factor, epidermal growth factor, and insulin, even in the absence of amino acids and glucose (Figure 5B). In SIN1−/− cells, Akt-Ser473 phosphorylation was not induced by any type of stimulus." provenance.
• _5 value "Akt Ser473 was strongly induced in wild-type cells by different growth factors such as the platelet-derived growth factor, epidermal growth factor, and insulin, even in the absence of amino acids and glucose (Figure 5B). In SIN1−/− cells, Akt-Ser473 phosphorylation was not induced by any type of stimulus." provenance.
• _8 value "The best-established function of pVHL to date has been as a substrate recognition component of an E3 ubiquitinprotein ligase complex, comprising pVHL, Elongin C, Elongin B, Cullin 2 and the RING finger protein, Rbx1, and this is referred to as the VCB–Cul2 complex [17]." provenance.
• _7 value "In this setting, pVHL targets the α-subunits of hypoxiainducible factor (HIF) for ubiquitin-mediated proteolysis under normal oxygen conditions [18]." provenance.
• _14 value "The stabilization of HIF in response to hypoxia involves the inactivation of prolylhydroxylases that modify HIF at specific proline residues in an oxygendependent manner. Proline hydroxylation marks HIF for degradation by the VCB–Cul2 E3 ligase complex (Figure 3 and Box 1)." provenance.
• _4 value "The VHL-mediated proteolytic degradation of HIF suppresses a transcription programme that is normally engaged by HIF as part of the adaptive response of the cell to hypoxia, such as the activation of vascular endothelial growth factor (VEGF), which is a potent angiogenic factor that is involved in the formation and differentiation of blood vessels." provenance.
• _6 value "Hydroxylation at two proline residues on the HIF polypeptide mediates interactions between the b-domain of the von Hippel–Lindau protein (pVHL) and HIF [60]. Each site can interact independently with pVHL, potentially contributing to the extremely rapid proteolysis of HIF-a that is observed under normoxic conditions. These sites contain a conserved LxxLAP motif and are targeted by proline hydroxylases (PHD) that, in mammalian cells, are provided by three isoforms termed PHD 1–3 [61]." provenance.
• _5 value "These hydroxylases are all Fe(II)- and 2-oxoglutarate-dependent dioxygenases that require molecular oxygen. Therefore, HIFa becomes stabilized under hypoxic conditions in which oxygen availability is low." provenance.
• _5 value "These hydroxylases are all Fe(II)- and 2-oxoglutarate-dependent dioxygenases that require molecular oxygen. Therefore, HIFa becomes stabilized under hypoxic conditions in which oxygen availability is low." provenance.
• _5 value "These hydroxylases are all Fe(II)- and 2-oxoglutarate-dependent dioxygenases that require molecular oxygen. Therefore, HIFa becomes stabilized under hypoxic conditions in which oxygen availability is low." provenance.
• _4 value "The overproduction of TGF-a in RCC cells is, at least in part, HIF-dependent and a major contributory event that confers a growth advantage to these cells [25,27]." provenance.
• _7 value "In particular, it has been reported that RCC cells can be sensitized to TNF-a-induced cytotoxicity by re-introducing wild-type VHL [38]. The authors highlight the fact that TNFreceptor engagement by TNF-a triggers the activation of atypical protein kinase C (aPKC), which, through IKKb phosphorylation, liberates NFkB, thereby initiating the transcription of genes that are involved in apoptosis" provenance.
• _6 value "In particular, it has been reported that RCC cells can be sensitized to TNF-a-induced cytotoxicity by re-introducing wild-type VHL [38]. The authors highlight the fact that TNFreceptor engagement by TNF-a triggers the activation of atypical protein kinase C (aPKC), which, through IKKb phosphorylation, liberates NFkB, thereby initiating the transcription of genes that are involved in apoptosis" provenance.
• _6 value "The regulation of insulin growth factor (IGF)-I-mediated cell invasion of RCC cells appears to be dependent upon PKCd inhibition by pVHL. This inhibition is mediated through a protein–protein interaction involving a domain of pVHL that shows similarity to protein kinase inhibitor (PKI), a natural inhibitor of cAMP-dependent protein kinase (PKA) [48]" provenance.
• _5 value "In contrast to protein-binding inhibition, evidence has shown that pVHL binds to both atypical PKC isoforms (l and z) through its b-domain, and in the case of activated aPKCl, mediates its turnover as part of the E3-ligase function of pVHL [39,40]. Although the functional significance of this inhibition remains elusive, given the central role for atypical PKCs (especially aPKCz) in establishing cell polarity in conjunction with PAR6 and the GTPase CDC42 [49], one could envisage a scenario whereby the loss of pVHL leads to altered cell polarity and, by extension, aberrant cell migration." provenance.
• _6 value "This same study demonstrated that the loss of VHL function negatively regulates tissue inhibitor of metalloproteinase 2 (TIMP-2), resulting in the upregulation of matrix metalloproteinase 2 (MMP2) and MMP9, thereby implicating pVHL in the control of these molecules." provenance.
• _4 value "Importantly, it has been demonstrated that hypoxia promotes tumour cell invasion by inducing the expression of the Met receptor [54]. This establishes a mechanism whereby transformed cells can be spurred to exit a hypoxic microenvironment and invade the surrounding tissues, which provide more favourable growth conditions. Because HIF-1a is involved in Met gene expression, the constitutive activation of HIF-1a as a consequence of pVHL deregulation provides a mechanism explaining the observation that the expression of HGF and Met receptor is associated with genetic alterations of VHL in primary RCC." provenance.
• _6 value "Importantly, it has been demonstrated that hypoxia promotes tumour cell invasion by inducing the expression of the Met receptor [54]. This establishes a mechanism whereby transformed cells can be spurred to exit a hypoxic microenvironment and invade the surrounding tissues, which provide more favourable growth conditions. Because HIF-1a is involved in Met gene expression, the constitutive activation of HIF-1a as a consequence of pVHL deregulation provides a mechanism explaining the observation that the expression of HGF and Met receptor is associated with genetic alterations of VHL in primary RCC." provenance.
• _4 value "Importantly, it has been demonstrated that hypoxia promotes tumour cell invasion by inducing the expression of the Met receptor [54]. This establishes a mechanism whereby transformed cells can be spurred to exit a hypoxic microenvironment and invade the surrounding tissues, which provide more favourable growth conditions. Because HIF-1a is involved in Met gene expression, the constitutive activation of HIF-1a as a consequence of pVHL deregulation provides a mechanism explaining the observation that the expression of HGF and Met receptor is associated with genetic alterations of VHL in primary RCC." provenance.
• _6 value "The fact that CXCR4 is a hypoxia-inducible gene provided a potential mechanistic explanation for CXCR4 upregulation during tumour cell evolution. CXCR4- induced cell-surface expression due to the loss of VHL function confers enhanced migratory potential to RCC cells in response to its cognate ligand stromal-derived factor 1 (SDF1)." provenance.
• _6 value "These modifications render Ras functional and capable of localizing to the lipid-rich inner surface of the cell membrane. The first and most critical modification, farnesylation, which is principally catalyzed by protein FTase, adds a 15-carbon hydrobobic farnesyl isoprenyl tail to the carboxyl terminus of Ras." provenance.
• _5 value "The considerable attention paid to targeting Ras as a therapeutic strategy is based on the high incidence of activating ras mutations in human malignancies, including approximately 22% of non–small-cell lung, 50% of colorectal, and 90% of pancreatic cancers. 53,60,61" provenance.
• _7 value "Localization of GTP-bound Ras to the inner surface of the cell membrane activates several downstream effectors, most notably the serine/threonine kinase Raf, which is the first signaling element in the MAPK pathway. 2,67,68 As shown in Figure 1, other downstream effectors of Ras include the PI3K cell survival pathway, the small GTP-binding proteins Rac and Rho, and the stress-activated protein kinase pathway (also referred to as the c-jun N-terminal kinase [JNK] pathway). 69-71 In addition, in response to cellular stress and cytokine stimulation mediated through Ras, the dual-specificity p38MAPK kinases (MKK3 and MKK6) and the JNK kinases (MKK4 and MKK7) phosphorylate p38MAPK and JNK, respectively. 72-76" provenance.
• _7 value "Localization of GTP-bound Ras to the inner surface of the cell membrane activates several downstream effectors, most notably the serine/threonine kinase Raf, which is the first signaling element in the MAPK pathway. 2,67,68 As shown in Figure 1, other downstream effectors of Ras include the PI3K cell survival pathway, the small GTP-binding proteins Rac and Rho, and the stress-activated protein kinase pathway (also referred to as the c-jun N-terminal kinase [JNK] pathway). 69-71 In addition, in response to cellular stress and cytokine stimulation mediated through Ras, the dual-specificity p38MAPK kinases (MKK3 and MKK6) and the JNK kinases (MKK4 and MKK7) phosphorylate p38MAPK and JNK, respectively. 72-76" provenance.
• _7 value "Localization of GTP-bound Ras to the inner surface of the cell membrane activates several downstream effectors, most notably the serine/threonine kinase Raf, which is the first signaling element in the MAPK pathway. 2,67,68 As shown in Figure 1, other downstream effectors of Ras include the PI3K cell survival pathway, the small GTP-binding proteins Rac and Rho, and the stress-activated protein kinase pathway (also referred to as the c-jun N-terminal kinase [JNK] pathway). 69-71 In addition, in response to cellular stress and cytokine stimulation mediated through Ras, the dual-specificity p38MAPK kinases (MKK3 and MKK6) and the JNK kinases (MKK4 and MKK7) phosphorylate p38MAPK and JNK, respectively. 72-76" provenance.
• _5 value "Localization of GTP-bound Ras to the inner surface of the cell membrane activates several downstream effectors, most notably the serine/threonine kinase Raf, which is the first signaling element in the MAPK pathway. 2,67,68 As shown in Figure 1, other downstream effectors of Ras include the PI3K cell survival pathway, the small GTP-binding proteins Rac and Rho, and the stress-activated protein kinase pathway (also referred to as the c-jun N-terminal kinase [JNK] pathway). 69-71 In addition, in response to cellular stress and cytokine stimulation mediated through Ras, the dual-specificity p38MAPK kinases (MKK3 and MKK6) and the JNK kinases (MKK4 and MKK7) phosphorylate p38MAPK and JNK, respectively. 72-76" provenance.
• _5 value "Localization of GTP-bound Ras to the inner surface of the cell membrane activates several downstream effectors, most notably the serine/threonine kinase Raf, which is the first signaling element in the MAPK pathway. 2,67,68 As shown in Figure 1, other downstream effectors of Ras include the PI3K cell survival pathway, the small GTP-binding proteins Rac and Rho, and the stress-activated protein kinase pathway (also referred to as the c-jun N-terminal kinase [JNK] pathway). 69-71 In addition, in response to cellular stress and cytokine stimulation mediated through Ras, the dual-specificity p38MAPK kinases (MKK3 and MKK6) and the JNK kinases (MKK4 and MKK7) phosphorylate p38MAPK and JNK, respectively. 72-76" provenance.
• _5 value "Raf is also activated by Ras-independent activators, including the soluble non-RTK Src and Janus kinase 1, which are involved in cytokine signaling.86 Other Ras-independent activators of Raf include interferon beta, protein kinase C (PKC) alpha, antiapoptotic proteins (eg, Bcl-2), scaffolding proteins (eg, ceramide-activated protein kinase), ultraviolet light, ionizing radiation, retinoids, erythropoietin, and dimerization between Raf isoforms 86-94 (Fig 3)." provenance.
• _6 value "Raf is also activated by Ras-independent activators, including the soluble non-RTK Src and Janus kinase 1, which are involved in cytokine signaling.86 Other Ras-independent activators of Raf include interferon beta, protein kinase C (PKC) alpha, antiapoptotic proteins (eg, Bcl-2), scaffolding proteins (eg, ceramide-activated protein kinase), ultraviolet light, ionizing radiation, retinoids, erythropoietin, and dimerization between Raf isoforms 86-94 (Fig 3)." provenance.
• _7 value "Additional support for the diverse functionality of Raf family members is provided by the disparate responses of B-Raf and C-Raf to identical stimuli, as well as the distinct messages that each isoform relays downstream to Rap1, which is a small GTPase that functions as both an activator and repressor of Raf.115 Rap1-mediated stimulation of B-Raf by cyclic adenosine monophosphate (cAMP) phosphorylates ERK, whereas stimulation of C-Raf inhibits ERK phosphorylation.115" provenance.
• _7 value "With regard to differences in signaling between the Raf isoforms, A-Raf is a weaker activator of MEK than B-Raf or C-Raf. Furthermore, A-Raf can activate MEK1 only, whereas C-Raf activates both MEK1 and MEK2.123-125" provenance.
• _9 value "C-Raf exists in the cytoplasm as a 300- to 500-kd protein complex. The complex consists of C-Raf, heat shock protein 90 (Hsp90), and the dimeric protein cofactor 14-3-3. 14-3-3 binds to two specific phosphoserine residues of C-Raf, which masks its kinase domain and inactivates the protein. The binding of Ras to C-Raf displaces the 14-3-3 dimer, rendering C-Raf accessible to dephosphorylation by protein phosphatase 2A.126" provenance.
• _7 value "The effector domain of GTP-bound Ras binds to C-Raf through the RBD and CRD in the CR1. Although binding to both sites is required for Raf activation, the most critical interaction is between Ras-GTP and the RBD.127 All Ras isoforms are capable of interacting with Raf, but K-Ras is the most potent activator, whereas N-Ras is much more efficient than H-Ras.128 The interaction between Ras and C-Raf alone is insufficient to activate C-Raf, but it serves to translocate C-Raf to the cell membrane where it can be activated." provenance.
• _7 value "The effector domain of GTP-bound Ras binds to C-Raf through the RBD and CRD in the CR1. Although binding to both sites is required for Raf activation, the most critical interaction is between Ras-GTP and the RBD.127 All Ras isoforms are capable of interacting with Raf, but K-Ras is the most potent activator, whereas N-Ras is much more efficient than H-Ras.128 The interaction between Ras and C-Raf alone is insufficient to activate C-Raf, but it serves to translocate C-Raf to the cell membrane where it can be activated." provenance.
• _8 value "The activation of B-Raf by Ras has been less well studied; however, the interacting amino acids in the Ras-Raf interface are identical for B-Raf and C-Raf.129,130 The association of Ras with B-Raf also translocates B-Raf to the cell membrane where it is activated.124 Interestingly, a membrane-free complex of B-Raf and 14-3-3 can be activated in vitro by recombinant Ras. This is in stark contrast to A-Raf and C-Raf, which must undergo a series of phosphorylation reactions on serine and tyrosine residues in the cell membrane and cannot be activated by Ras alone.124,130 Of the Raf isoforms, B-Raf is activated first, and on stimulation by Ras, it heterodimerizes with C-Raf, the significance of which is not known.94" provenance.
• _7 value "Both B-Raf and C-Raf can bind to other small GTPases, most notably Rap1.115,131,132 The effector domains of Rap1 and Ras are nearly identical, but activation of these proteins produces vastly different downstream effects. Furthermore, Rap1 mediates distinct effects after binding to various Raf isoforms. The B-Raf–Rap1 complex activates B-Raf, whereas the C-Raf–Rap1 interaction does not activate C-Raf and, in fact, may be inhibitory.115,132,133 This occurs because Rap1 binds to the CRD of C-Raf with higher affinity than Ras and excludes Ras from binding." provenance.
• _10 value "The Rho family of small GTPases, consisting of Rho, Rac, and cyclin-dependent kinase (Cdc) 42, regulate cytoskeletal organization during the cell cycle and also mediate Ras-induced activation of Raf, especially C-Raf.134-136 These GTPases do not directly bind to Raf but, instead, signal by activating downstream kinases. Rho signals by activating the serine/threonine protein kinases N1 and N2 and Rho-associated kinase 1, whereas Rac and Cdc42 signal through p21-activated kinase (PAK).134-136" provenance.
• _6 value "Phosphorylation. Raf is principally activated by phosphorylation of specific amino acid residues as shown for each isoform in Figure 4. From an evolutionary standpoint, the Raf activation sites are highly conserved from yeast to humans. Several amino acids in Raf, particularly serine (S) 259 and S621, which bind 14-3-3 and maintain C-Raf in a closed auto-inhibited conformation, are phosphorylated in the basal state.137 On stimulation, Ras-GTP displaces 14-3-3 from S259, and C-Raf is translocated to the cell membrane, where it can be dephosphorylated at S259 by protein phosphatase 2A or other phosphatases.126 S259 also represents the site of inhibitory phosphorylation by PKB/Akt, PKA, and serum glucocorticoid-inducible kinase.121,138,139 Phosphorylation at S621 seems to have greater significance because mutations at this site inactivate Raf's kinase activity. Hence, a balance of phosphorylation and dephosphorylation is required to prime Raf in the basal state before stimulation by Ras or mitogens.137" provenance.
• _6 value "Phosphorylation. Raf is principally activated by phosphorylation of specific amino acid residues as shown for each isoform in Figure 4. From an evolutionary standpoint, the Raf activation sites are highly conserved from yeast to humans. Several amino acids in Raf, particularly serine (S) 259 and S621, which bind 14-3-3 and maintain C-Raf in a closed auto-inhibited conformation, are phosphorylated in the basal state.137 On stimulation, Ras-GTP displaces 14-3-3 from S259, and C-Raf is translocated to the cell membrane, where it can be dephosphorylated at S259 by protein phosphatase 2A or other phosphatases.126 S259 also represents the site of inhibitory phosphorylation by PKB/Akt, PKA, and serum glucocorticoid-inducible kinase.121,138,139 Phosphorylation at S621 seems to have greater significance because mutations at this site inactivate Raf's kinase activity. Hence, a balance of phosphorylation and dephosphorylation is required to prime Raf in the basal state before stimulation by Ras or mitogens.137" provenance.
• _6 value "Raf is also phosphorylated at other serine and threonine residues, the most important of which are S338 and tyrosine (Y) 341, which are situated adjacent to the C-Raf kinase domain.140 Phosphorylation of these residues relieves the inhibitory effects of the regulatory domain on the kinase domain.141 S338, which is the evolutionarily conserved PAK phosphorylation site that resides on the amino-terminal side of the kinase domain, is critical for Raf activation.134-136,140,142 This site is also phosphorylated in response to stimulation by growth factors, integrins, Ras, PAK1, and PAK3.78,136,143" provenance.
• _6 value "Raf is also phosphorylated at other serine and threonine residues, the most important of which are S338 and tyrosine (Y) 341, which are situated adjacent to the C-Raf kinase domain.140 Phosphorylation of these residues relieves the inhibitory effects of the regulatory domain on the kinase domain.141 S338, which is the evolutionarily conserved PAK phosphorylation site that resides on the amino-terminal side of the kinase domain, is critical for Raf activation.134-136,140,142 This site is also phosphorylated in response to stimulation by growth factors, integrins, Ras, PAK1, and PAK3.78,136,143" provenance.
• _5 value "As shown in Figure 2, C-Raf interacts with a diverse array of scaffolding proteins (kinase suppressor of Ras and MEK partner-1), adaptor proteins (Bcl-2–associated athanogene-1), chaperone proteins (Hsp90 and Hsp70), substrates (retinoblastoma protein [Rb]), lipids (phosphatidic acid, cholesterol-rich caveolae, and cytosolic lipid rafts), and cellular constituents, many of which, in turn, modulate its kinase activity.95" provenance.
• _5 value "As shown in Figure 2, C-Raf interacts with a diverse array of scaffolding proteins (kinase suppressor of Ras and MEK partner-1), adaptor proteins (Bcl-2–associated athanogene-1), chaperone proteins (Hsp90 and Hsp70), substrates (retinoblastoma protein [Rb]), lipids (phosphatidic acid, cholesterol-rich caveolae, and cytosolic lipid rafts), and cellular constituents, many of which, in turn, modulate its kinase activity.95" provenance.
• _5 value "As shown in Figure 2, C-Raf interacts with a diverse array of scaffolding proteins (kinase suppressor of Ras and MEK partner-1), adaptor proteins (Bcl-2–associated athanogene-1), chaperone proteins (Hsp90 and Hsp70), substrates (retinoblastoma protein [Rb]), lipids (phosphatidic acid, cholesterol-rich caveolae, and cytosolic lipid rafts), and cellular constituents, many of which, in turn, modulate its kinase activity.95" provenance.
• _5 value "As shown in Figure 2, C-Raf interacts with a diverse array of scaffolding proteins (kinase suppressor of Ras and MEK partner-1), adaptor proteins (Bcl-2–associated athanogene-1), chaperone proteins (Hsp90 and Hsp70), substrates (retinoblastoma protein [Rb]), lipids (phosphatidic acid, cholesterol-rich caveolae, and cytosolic lipid rafts), and cellular constituents, many of which, in turn, modulate its kinase activity.95" provenance.
• _7 value "The Raf isoforms are the best characterized MEK1 and MEK2 activators, and all Raf isoforms activate MEK1, whereas only B-Raf and C-Raf activate MEK2. MEK1 and MEK2 contain a proline-rich sequence that enables recognition and activation by Raf.125,146-153." provenance.
• _7 value "The Raf isoforms are the best characterized MEK1 and MEK2 activators, and all Raf isoforms activate MEK1, whereas only B-Raf and C-Raf activate MEK2. MEK1 and MEK2 contain a proline-rich sequence that enables recognition and activation by Raf.125,146-153." provenance.
• _7 value "The Raf isoforms are the best characterized MEK1 and MEK2 activators, and all Raf isoforms activate MEK1, whereas only B-Raf and C-Raf activate MEK2. MEK1 and MEK2 contain a proline-rich sequence that enables recognition and activation by Raf.125,146-153." provenance.
• _7 value "the dual-specificity p38MAPK kinases (MKK3 and MKK6) and JNK kinases (MKK4 and MKK7) phosphorylate p38MAPK and JNK, respectively.72-76" provenance.
• _6 value "Cell survival signaling is also regulated by C-Raf, which induces phosphorylation of Iκ B in the NF-κB–Iκ B complex. This action releases activated NF-κB, which is then translocated to the nucleus where it mediates transcription of antiapoptotic factors.155,166" provenance.
• _6 value "In addition, C-Raf phosphorylates Rb, p53, Cdc25, and other cell cycle regulatory proteins in metaphase.156,170,171 Lastly, C-Raf induces transcription of the multidrug resistance gene mdr-1, and its activation has been associated with multidrug resistance.172" provenance.
• _9 value "Originally identified by high-throughput screening of small molecules against C-Raf kinase, sorafenib was found to be a potent competitive inhibitor of ATP binding in the catalytic domains of C-Raf, wild-type B-Raf, and V599EB-Raf mutant." provenance.
• _5 value "cAMP is of pivotal importance in determining many aspects of cellular function [1,2]. It is generated at the cytosol surface of the plasma membrane through the action of adenylate cyclases, of which there is a large family. Increased levels of cAMP are translated into cellular responses through the action of cAMP-dependent protein kinase (PKA)" provenance.
• _6 value "The third subdomain of the catalytic unit of all PDE4 subfamilies, but not that of PDE4A, contains a single, ERK consensus motif (Pro-Xaa-Ser-Pro). The serine residue in this site can be phosphorylated, both in vitro and in vivo , by ERK [49,70,71]." provenance.
• _6 value "The third subdomain of the catalytic unit of all PDE4 subfamilies, but not that of PDE4A, contains a single, ERK consensus motif (Pro-Xaa-Ser-Pro). The serine residue in this site can be phosphorylated, both in vitro and in vivo , by ERK [49,70,71]." provenance.
• _7 value "In these cells ERK causes the autocrine generation of prostaglandin E2 (PGE2) through activation of PKA2 and the production of arachidonic acid. Thus the rapidly generated PGE2 stimulates adenylate cyclase, increasing cAMP levels," provenance.
• _5 value "In these cells ERK causes the autocrine generation of prostaglandin E2 (PGE2) through activation of PKA2 and the production of arachidonic acid. Thus the rapidly generated PGE2 stimulates adenylate cyclase, increasing cAMP levels," provenance.
• _5 value "PA causes a marked (0.7-3-fold) activation of various long PDE4 isoforms, but fails to affect short and super-short isoforms [87,91]. Similar activation was seen with the acidic phospholipid phosphatidylserine (PS), but not with neutral phospholipids." provenance.
• _4 value "Like progesterone receptors (PR), Stat5a and 5b are required for normal mammary gland growth and differentiation. These two proteins are up-regulated during pregnancy, a period dominated by high levels of progesterone." provenance.
• _4 value "Like progesterone receptors (PR), Stat5a and 5b are required for normal mammary gland growth and differentiation. These two proteins are up-regulated during pregnancy, a period dominated by high levels of progesterone." provenance.
• _6 value "In addition, progestin treatment induces translocation of Stat5 into the nucleus, possibly mediated by the association of PR and Stat5. Last, progesterone pretreatment enhances the phosphorylation of Stat5 on tyrosine 694 induced by epidermal growth factor." provenance.
• _4 value "Similar studies using anti-Stat3 (Fig. 2B) and anti-Stat1 (Fig. 2C) antibodies show that these STAT family members are also progestin regulated. While Stat3 is clearly up-regulated by progestin treatment, Stat1 is slightly down-regulated." provenance.
• _5 value "These reciprocal studies show that PR and Stat5 are associated, either directly or in a multiprotein complex." provenance.
• _6 value "However, Stat5 remained unphosphorylated (P-Stat5, lanes 1–5), except in the cells that were pretreated with R5020 for 48 h, prior to the 10-min prolactin treatment (P-Stat5, lane 6). Prolactin alone had no effect (lane 3) nor did transient (1 h) or chronic (48 h) R5020 treatment (lane 2). Thus, in T47Dco cells, Stat5 phosphorylation by prolactin requires progesterone pretreatment." provenance.
• _7 value "The β-casein promoter, known to be induced by Stat5 when activated by prolactin via prolactin receptors and JAK2, was next used to test the function of the phosphorylated Stat5. T47D-YB cells were pretreated with either R5020 or ethanol vehicle for 48 h. Cells were then washed, transfected with a β-casein promoter-luciferase reporter, treated with either R5020 or prolactin, and harvested for luciferase assay 24 h after hormone treatment. We found that in T47D-YB breast cancer cells, prolactin alone has minimal to no significant effect on the β-casein luciferase promoter. However, after R5020 pretreatment, a 6–7-fold induction of the β-casein luciferase promoter was observed (Fig.7B). Thus R5020 sensitized these breast cancer cells to the transcriptional effects of prolactin mediated through Stat5." provenance.
• _6 value "The β-casein promoter, known to be induced by Stat5 when activated by prolactin via prolactin receptors and JAK2, was next used to test the function of the phosphorylated Stat5. T47D-YB cells were pretreated with either R5020 or ethanol vehicle for 48 h. Cells were then washed, transfected with a β-casein promoter-luciferase reporter, treated with either R5020 or prolactin, and harvested for luciferase assay 24 h after hormone treatment. We found that in T47D-YB breast cancer cells, prolactin alone has minimal to no significant effect on the β-casein luciferase promoter. However, after R5020 pretreatment, a 6–7-fold induction of the β-casein luciferase promoter was observed (Fig.7B). Thus R5020 sensitized these breast cancer cells to the transcriptional effects of prolactin mediated through Stat5." provenance.
• _5 value "Fig. 8C shows that the c-fos promoter is induced 19.3-fold by R5020 and 6.2-fold by EGF. Remarkably, together the two hormones produced a 145-fold increase in luciferase activity." provenance.
• _4 value "Fig. 8C shows that the c-fos promoter is induced 19.3-fold by R5020 and 6.2-fold by EGF. Remarkably, together the two hormones produced a 145-fold increase in luciferase activity." provenance.
• _6 value "Progesterone enhances the ability of EGF to phosphorylate Stat5 on tyrosine 694." provenance.
• _3 value "They can also trigger hepatic necrosis and/or apoptosis, causing cytolytic hepatitis, which can evolve into liver failure." provenance.
• _3 value "During the fasting state, fatty acid oxidation (FAO) in the liver is incomplete; the acetyl-CoA that is generated is not oxidized in the liver, but condenses into ketone bodies (mainly acetoacetate and β-hydroxybutyrate) (Figure 1), which are released into the plasma for subsequent oxidation in extrahepatic tissues." provenance.

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