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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acute phase proteins (APPs) have been empirically defined as those whose plasma concentration changes following inflammatory reaction. Those proteins whose concentrations increase are referred to as positive APP, while those whose levels decline are termed negative APP. In man, positive APP are: alpha 1 acid glycoprotein, alpha 1 protease inhibitor, alpha 1 antichymotrypsin, haptoglobin, ceruloplasmin, fibrinogen, C-reactive protein, serum amyloid A. Great variability in the APP response between different species is observed. The principal functions of APP, result from the interaction of these proteins with ligands of various origins which give "protein-ligands" complexes. These complexes are cleared by the RES or by the hepatocyte. The results are protease inhibition, neutralization of toxic molecules such as hemoglobin or the superoxide anion, clearance of cell membranes and chromatin. The drop of the plasma concentration of negative APP during an inflammatory reaction carries a rise of free ligands (fatty acids, hormones, vitamins, trace elements). IL6 has been recognized as the principal regulator of most APP genes. The response of the hepatic cell to IL6 is characterized by the enhanced production of type 2 or IL6 specific APPs. The biochemical process of signal transduction is IL6--JAK2--APRF The set of APP genes regulated by IL1 type cytokines (type 1 APPs) is distinct from that regulated by IL6 type cytokine. IL1 and TNF alpha mediated stimulation of type 1 APP genes is synergistically enhanced by IL6 type cytokines. The biochemical process of signal transduction is IL1, IL6--Ras--MAP kinase--NFIL6 The targeted inflammatory proteic profile including the assay of C-reactive protein, haptoglobin and alpha 1 acid glycoprotein produces a "biological tool" to the clinician in order to manage an inflammatory response. IL6, a proteic marker for the future, connected with CRP, will be assayed during early inflammatory reaction.
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PMID:[Acute-phase proteins in inflammation]. 856 70

A decline in plasma concentration of insulin-like growth factor-1 (IGF-1) has been hypothesized to contribute to a decrease in tissue protein synthesis and function in aging animals and man. In this study, the effects of aging and long-term caloric restriction on growth hormone receptor signal transduction were assessed in hepatic tissue to determine whether alterations in tissue responsiveness to growth hormone contribute to the decline in IGF-1 gene expression. Liver slices from female C57/BL mice (10, 17, and 31 months) were prepared in media and stimulated with growth hormone (2 nM). An increase in growth hormone receptor binding was observed in 31-month ad libitum-fed animals (p < .01) compared to 10- or 17-month-old animals), and this effect was partially attenuated by moderate caloric restriction. However, growth hormone (2 nM)-induced IGF-1 gene expression was significantly lower in old ad libitum-fed animals (p < .05 compared to 10-month-old ad libitum and 31-month-old caloric-restricted animals). Further analysis revealed that growth hormone receptor and JAK2 kinase phosphorylation as well as mitogen-activated protein (MAP) kinase activity were significantly lower in old animals compared to the adult or middle-age groups (p < .05). Old caloric-restricted animals demonstrated a significant increase in growth hormone receptor and JAK2 kinase phosphorylation and MAP kinase activity in response to growth hormone. The results demonstrate that growth hormone increases growth hormone receptor and JAK2 kinase phosphorylation as well as MAP kinase activity in liver. These responses decrease with age and are attenuated by moderate, long-term caloric restriction.
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PMID:Moderate caloric restriction prevents the age-related decline in growth hormone receptor signal transduction. 861 1

AP-1 is a collection of dimeric sequence specific, DNA binding, transcriptional activators composed of Jun and Fos subunits. The composition, the level and the activity of AP-1 complexes are regulated in response to extracellular stimuli. An important role in this regulation is played by mitogen-activated protein kinases (MAPKs). The specific roles of three MAPKs, namely ERK, JNK and FRK, in modulation of both the level and activity of AP-1, are discussed.
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PMID:The regulation of AP-1 activity by mitogen-activated protein kinases. 865 Feb 58

Cell adhesion to the extracellular matrix triggers a cascade of intracellular biochemical signals regulated by the integrin family of receptors. Recent evidence suggests that integrin engagement may activate a mitogen-activated protein (MAP) kinase cascade that may cooperate with more clearly defined mitogenic signaling pathways to regulate cell proliferation, adhesion, and migration. Here we report that the adhesion-dependent activation of the MAP kinase Erk2 (extracellular signal-regulated kinase 2) occurs in serum-starved NIH3T3 cells, and that this activation of Erk2 is preceded by the activation of the small GTP-binding protein Ras in fibronectin-adherent cells. Inhibition of Ras signaling by expression of a dominant-inhibitory mutant of Ras (N17Ras) in NIH3T3 cells blocked adhesion-dependent activation of Erk2, although the focal adhesion kinase (FAK) was still activated in these cells. Furthermore, activation of this Ras-MAP kinase pathway activated cytosolic phospholipase A2, leading to the release of arachidonic acid metabolites, and N17Ras also inhibited these events. However, N17Ras expression does not inhibit cell adhesion, spreading, or focal contact and stress fiber formation. These results suggest that, while integrin-dependent activation of this MAP kinase pathway is Ras-dependent, the integrin-dependent activation of FAK and several morphological events are Ras-independent. Thus, integrin-mediated signals involved in regulating cell morphology appear to diverge from those regulating MAP kinase activation at a level upstream of Ras activation.
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PMID:Ras activation is necessary for integrin-mediated activation of extracellular signal-regulated kinase 2 and cytosolic phospholipase A2 but not for cytoskeletal organization. 866 48

The integrins are a family of cell surface receptors that mediate adhesive interactions with the extracellular matrix and also generate signals that influence cell growth and differentiation. Ligation and clustering of integrins causes activation and autophosphorylation of focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase, and results in the transient activation of p42 and p44 mitogen-activated protein (MAP) kinases. Initial evidence has suggested that the integrin signaling pathway may share common elements with the canonical Ras signal transduction cascade activated by peptide mitogens such as epidermal growth factor (EGF). In this report we demonstrate that Raf-1 and MAP or extracellular signal-related kinase kinase (MEK), key cytoplasmic kinases of the Ras cascade, are activated subsequent to integrin-mediated adhesion of mouse NIH 3T3 fibroblasts. We also show that MAP kinase is downstream of MEK in the integrin signaling pathway. However, in contrast to the receptor tyrosine kinase signaling cascade, integrin-mediated signal transduction seems to be largely independent of Ras. Dominant negative inhibitors of Ras-dependent signaling failed to block integrin-mediated activation of MEK. In addition, while treatment with the peptide mitogen EGF clearly increased GTP-loading of Ras, little effect was observed in response to integrin-dependent cell adhesion. Thus, integrin-mediated activation of MEK and MAP kinase in 3T3 cells occurs primarily by a mechanism that is distinct from the Ras signal transduction cascade.
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PMID:Integrin-mediated activation of MEK and mitogen-activated protein kinase is independent of Ras [corrected]. 866 36

Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction-driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3-dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2-STAT3/STAT5.
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PMID:Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer. 869 59

Interleukin-11 is a stromal derived cytokine important in hematopoiesis. IL-11 intracellular signaling travels through cytoplasmic kinases of the Janus family. How JAKs accomplish the multiple functions of IL-11 has not been determined and until recently only a few associated downstream proteins have been identified. We present evidence here for the IL-11 induced association of PP2A, P13K, and Yes to JAK2. Reciprocal immunoprecipitations support the mutual involvement of these signaling components in IL-11 mediated signal transduction. This novel finding of JAK2/PP2A binding and release may have relevance to many serine/threonine regulated mechanisms such as P13K, Stat, and MAPK activation. These associations support a model of JAK2 as a protein kinase docking protein of IL-11 signal transduction that may be applicable to other gp130 and JAK signal transduction systems.
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PMID:Complex formation of JAK2 with PP2A, P13K, and Yes in response to the hematopoietic cytokine interleukin-11. 870 85

Local alterations in the hemodynamic environment regulate endothelial cell function, but the signal-transduction mechanisms involved in this process remain unclear. We previously demonstrated that mitogen-activated protein (MAP) kinase is rapidly stimulated by flow in bovine aortic endothelial cells. Integrin receptors may act as mechanotransducers, as suggested by rapid remodeling of focal adhesion complexes in response to flow. To study the role of integrins in flow-mediated MAP kinase activation, we compared the effects of beta 1 integrin activation (with 8A2 antibody) and flow in cultured human umbilical vein endothelial cells (HUVECs). Both 8A2 (3 micrograms/mL) and flow (shear stress, 12 dynes/cm2) stimulated MAP kinase, although the flow response was faster and greater. To characterize flow-activated tyrosine kinases, tyrosine-phosphorylated proteins were immunoprecipitated and identified by Western blot. There was a time-dependent increase in phosphotyrosine content in 60- to 80-kD, 110-kD, 125- to 150-kD, and 180- to 190-kD proteins. A 125-kD protein was identified as focal adhesion kinase (FAK), suggesting that flow activates integrins. In comparison with flow, 8A2 caused less tyrosine phosphorylation of fewer proteins, although FAK was tyrosine phosphorylated. Concurrent stimulation of HUVECs with 8A2 and flow caused additive increases in MAP kinase. Antibody 8A2 increased binding of the beta 1 affinity-sensitive antibody, 15/7, while flow failed to increase binding of 15/7. In summary, both a beta 1-activating antibody and flow stimulate tyrosine kinases, leading to activation of FAK and MAP kinase signal-transduction pathways. However, the cellular responses elicited by 8A2 represent only a portion of those stimulated by flow, suggesting that "costimulatory" events such as calcium mobilization, in addition to integrin activation, mediate the HUVEC response to fluid shear stress.
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PMID:MAP kinase activation by flow in endothelial cells. Role of beta 1 integrins and tyrosine kinases. 875 9

The peptide hormone prolactin (Prl) regulates proliferation of normal and malignant mammary cells. In the present study we demonstrate that two Prl responsive cell lines, NOG-8 and T47D, activate the JAK2-SHC-MAPK pathway in a rapid and transient manner. Within 1 min of Prl treatment there was an increase in association of JAK2 with SHC, followed by rapid phosphorylation of both the 52 kDa and 46 kDa SHC proteins. Grb2 and Sos associated with the SHC proteins within 1-3 min of Prl treatment in these mammary cells. Within 5 min of hormone treatment we observe an increase in ras-GTP suggesting activation of ras. We also showed a rapid and transient tyrosine phosphorylation of STAT5 in proliferating T47D cells which reached its peak after 30 min of Prl treatment. These results indicate that Prl receptors, after binding the ligand, activate several pathways for signal transduction leading to mitogenesis.
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PMID:Involvement of SHC, GRB2, SOS and RAS in prolactin signal transduction in mammary epithelial cells. 880 87

GH induces phosphorylation of a number of cellular proteins, of which several have now been identified, such as mitogen-activated protein kinase, insulin receptor substrate-1, and members of the JAK kinase and STAT families of proteins. However, other phosphorylated proteins remain unidentified. Growth factors and cytokines, including epidermal growth factor, insulin, pp60v-scr, and angiotensin II, induce a rapid phosphorylation of annexin I, a 35-kDa member of the annexin family of Ca2+ and phospholipid-binding proteins. The osteoblast-like rat osteosarcoma cell-line UMR-106.01, in which GH acts as a mitogen via a high affinity GH receptor, was used as a model for GH-induced protein phosphorylation. It is demonstrated by immunoblotting and immunoprecipitation techniques that GH induces the phosphorylation of annexin I on tyrosine residues. This phosphorylation is dose and time dependent. Induction of annexin I phosphorylation is delayed compared with that of JAK2. These results identify annexin I as a protein that becomes tyrosine phosphorylated under the influence of GH and show that phosphorylation of annexin I is a general phenomenon that follows activation of a cell by hormones or cytokines.
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PMID:Growth hormone induces tyrosine phosphorylation of annexin I in rat osteosarcoma cells. 882 96


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