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 high affinity receptor for GM-CSF consists of a unique alpha subunit and a beta subunit that is shared with receptors for IL-3 and IL-5. Activation of GM-CSF receptor (GMR) triggers two distinct cytoplasmic signalling pathways, JAK2 and Ras, and is sufficient to maintain proliferation of growth factor-dependent cell lines. Shc proteins are phosphorylated upon activation of GMR and may be involved in the transmission of GM-CSF signals to Ras. To define the role of Shc proteins in cells stimulated with GM-CSF, we investigated both the network of interactions that involve Shc after GM-CSF stimulation and the effects of overexpressing Shc proteins on the proliferative response to GM-CSF. Two cytoplasmic complexes, Grb2/Sos and Grb2/p140 bind through the Grb2 SH2 domain to phosphorylated Shc, and are thereby recruited to the beta subunit. Both complexes are stable, even in the absence of ligand, and depend on the direct association of p140 and Sos respectively with the SH3 domains of Grb2. p140 is an uncharacterized protein constitutively phosphorylated on tyrosine and, in its Grb2-bound form, expressed only in hematopoietic cells, the oligomeric complex formed by phosphorylated beta subunit-phosphorylated Shc-Grb2-SoS-p140 is also induced by IL-3 and L-5 stimulation of growth-factor dependent cell lines. Overexpression of wild-type Shc proteins in growth factor-dependent cells increases both MAP kinase activation and proliferation in response to GM-CSF. These effects require the association of Shc with Grb2. Taken together these results indicate that phosphorylation of Shc proteins is a crucial step in the transmission of GM-CSF proliferative stimuli, since it creates a high affinity binding site for the Grb2/SoS complex, whose function is to activate Ras and, for the Grb2/p140 complex, whose function remains unknown.
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PMID:Overexpression of Shc proteins potentiates the proliferative response to the granulocyte-macrophage colony-stimulating factor and recruitment of Grb2/SoS and Grb2/p140 complexes to the beta receptor subunit. 789 32

The GH receptor (GHR) is a member of the cytokine/hematopoietic growth factor family, and protein tyrosine phosphorylation has been implicated in the signaling cascade of these receptors. It was recently shown that the tyrosine kinase JAK2 is associated with the GHR. GH induces the activation of JAK2, which phosphorylates itself and the receptor. Mitogen-activated protein (MAP) kinase activation and transcriptional stimulation of specific genes, such as Spi 2.1, have also been reported to be induced by GH. To identify functionally important regions in the cytoplasmic domain of the GHR, we compared the actions of the wild-type receptor, two truncated mutants, and one internal deletion mutant (similar to the intermediate Nb2 form of the PRL receptor) in transfectants of the Chinese hamster ovary cell line. A region of 46 amino acids adjacent to the membrane was found to be sufficient for activation of both JAK2 and MAP kinases. This region contains a proline-rich sequence (box 1) conserved in the cytokine receptor family that is important for signal transduction. For transcriptional activity, the C-terminal region of the GHR is required, and we found that the last 80 terminal residues contain sequences allowing activation of the Spi 2.1 promoter. Tyrosine phosphorylation of the receptor also requires the C-terminal portion of the GHR cytoplasmic domain, and we found that GHR tyrosine phosphorylation appears to be linked to activation of the Spi 2.1 transcription pathway. Thus, the GHR could be composed of at least 2 functional regions: the 46 proximal amino acids required for activation of JAK2 and sufficient to stimulate the MAP kinase pathway, and an additional carboxy-terminal region necessary for transcriptional activation.
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PMID:Distinct cytoplasmic regions of the growth hormone receptor are required for activation of JAK2, mitogen-activated protein kinase, and transcription. 792 91

The erythropoietin receptor (EpoR) belongs to the cytokine receptor family, members of which lack a tyrosine kinase domain. Recent studies, however, have shown that a cytoplasmic tyrosine kinase, JAK2, interacts with the cytoplasmic domain of the EpoR and becomes activated upon binding of Epo to the receptor. Epo has also been shown to stimulate activation of Ras and Raf-1. The present studies were undertaken to examine the possible involvement of Epo-induced tyrosine phosphorylation in activation of the Ras/mitogen-activated protein kinase (MAP kinase) pathway and to determine its significance on the growth signaling from the EpoR. In an interleukin (IL)-3-dependent cell line expressing the transfected wild-type EpoR, Epo, or IL-3 induced tyrosine phosphorylation of Shc and its association with Grb2. These cytokines also induced tyrosine phosphorylation and activation of MAP kinase isoforms ERK1 and ERK2. A mutant EpoR with a carboxyl-terminal deletion of 108 amino acids (H mutant), which is mitogenically functional but lacks tyrosine phosphorylation sites in the carboxyl-terminal region, showed markedly diminished abilities to induce tyrosine phosphorylation of Shc and to phosphorylate and activate MAP kinases. A mutant receptor (PM4 mutant) inactivated by a point mutation, Trp282 to Arg, which abrogates the interaction with JAK2, failed to induce any effect on Shc or MAP kinases. In cells expressing a mutant EpoR that is constitutively activated by a point mutation, Arg129 to Cys, in the extracellular portion of the receptor, neither tyrosine phosphorylation of Shc nor activation of MAP kinases by phosphorylation was detectable without stimulation with Epo or IL-3. These results suggest that the carboxyl-terminal region of EpoR may play a crucial role in activation of MAP kinases through the Ras signaling pathway which may be activated by tyrosine phosphorylation of Shc and its association with Grb2. The activation of MAP kinases, however, failed to correlate with the mitogenic activity of mutant EpoRs and thus may not be required for growth signaling from the EpoR.
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PMID:Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. 796 95

We have previously shown that the IL-6R in a growth-responsive B cell line, AF10, induces activation of mitogen-activated protein (MAP) kinase. Here we demonstrate the activation of Raf-1 and MEK-1, which act as a MAP kinase kinase kinase and a MAP kinase kinase, respectively, in the MAP kinase cascade induced by IL-6 in AF10 cells. IL-6 also induced tyrosine phosphorylation of the signaling transducing subunit of the IL-6R in AF10 cells, along with tyrosine phosphorylation of the gp130-associated tyrosine protein kinase JAK1 and the adaptor molecule p52shc. Although induction of tyrosine phosphorylation and activation of MAP kinase by IL-6 in a differentiation-responsive B cell line, SKW 6.4, were below the limits of detection, the phorbol ester PMA did activate Raf-1, MEK-1, and MAP kinase without inducing the phosphorylation of gp130, JAKs, or p52shc. These results suggest that JAK kinase family members associated with the IL-6R may participate in the activation of MAP kinase in AF10 cells by way of an adaptor protein and Ras-dependent kinase cascade.
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PMID:Involvement of Janus kinases, p52shc, Raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth-responsive B cell line. 796 20

Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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PMID:Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. 852 13

A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Thr or Tyr, the majority are extremely sensitive to staurosporine, with IC50 values in the low nanomolar range. A few of them however, notably protein kinases CK1 and CK2, mitogen-activated protein (MAP) kinase and protein-tyrosine kinase CSK, are relatively refractory to staurosporine inhibition, exhibiting IC50 values in the micromolar range. With all protein kinases tested, namely PKA, CK1, CK2, MAP kinase (ERK-1), c-Fgr, Lyn, CSK and TPK-IIB/p38Syk, staurosporine inhibition was competitive with respect to ATP, regardless of its inhibitory power. In contrast, either uncompetitive or noncompetitive kinetics of inhibition with respect to the phosphoacceptor substrate were exhibited by Ser/Thr and Tyr-specific protein kinases, respectively, consistent with a different mechanism of catalysis by these two sub-families of kinases. Computer modeling based on PKA crystal structure in conjunction with sequence analysis suggest that the low sensitivity to staurosporine of CK2 may be accounted for by the bulky nature of three residues, Val66, Phe113 and Ile174 which are homologous to PKA Ala70, Met120 and Thr183, respectively. In contrast these PKA residues are either conserved or replaced by smaller ones in protein kinases highly sensitive to staurosporine inhibition. On the other hand, His160 which is homologous to PKA Glu170, appears to be responsible for the unique behaviour of CK2 with respect to a staurosporine derivative (CGP44171A) bearing a negatively charged benzoyl substituent: while CGP44171A is 10- 100-fold less effective than staurosporine against PKA and most of the other protein kinases tested, it is actually more effective than staurosporine for CK2 inhibition, but it looses part of its efficacy if it is tested on a CK2 mutant (H160D) in which His160 has been replaced by Asp. It can be concluded from these data that the catalytic sites of protein kinases are divergent enough as to allow a competitive inhibitor like staurosporine to be fairly selective, a feature that can be enhanced by suitable modifications designed based on the structure of the catalytic site of the kinase.
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PMID:Different susceptibility of protein kinases to staurosporine inhibition. Kinetic studies and molecular bases for the resistance of protein kinase CK2. 852 58

The growth hormone receptor (GHR) belongs to the superfamily of transmembrane proteins that includes the prolactin receptor and a number of cytokine receptors. Two forms exist for the GHR: the full-length membrane-bound human receptor is a protein of 620 amino acids with a single transmembrane region; and the GH binding protein (GHBP) is a short soluble from corresponding to the extracellular domain of the full-length receptor. In rodents, GHBP is encoded by a specific mRNA of 1.2-1.5 kb, whereas in man and other species GHBP is believed to result from proteolytic cleavage of the membrane receptor. Growth hormone binding protein prolongs the half-life of GH but other functions for GHBP remain to be demonstrated. Recombinant GHBP complexed to human GH shows a 2:1 stoichiometric crystal structure. Growth hormone-induced dimerization of the cell surface GHR appears to be a prerequisite for biological activity of the hormone. JAK2 has been identified as a tyrosine kinase associated with GHR and other receptors of the superfamily. Binding of GH to its receptor results in dimerization of the GHR, phosphorylation of JAK2 and of the GHR. Other substrates for JAK2 have to be identified. Transcription factors belonging to the STAT (signal transducers and activators of transcriptions) family are involved in the transcriptional effects of GH. The activity of mutants of the GHR has been measured in functional tests to identify sequences of the cytoplasmic domain of the receptor that are important for signal transduction. A proline-rich sequence, called Box I, conserved among members of the receptor family has been shown to be crucial for GH effects on gene transcription. MAP kinase activity and cell proliferation. The C-terminal region of the GHR is required for tyrosine phosphorylation of the receptor and for a hormonal effect on gene transcription, whereas only 46 membrane proximal amino acids of the cytoplasmic domain are necessary for activation of JAK2 and transduction of the GH proliferative signal. Much work remains to be done to identify other protein kinases and signalling molecules involved in the mechanism of action of GH.
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PMID:Growth hormone receptor: structure and signal transduction. 854 48

Thrombopoietin (Tpo) is a cytokine regulating megakaryocyte maturation and platelet formation. We studied Tpo-induced signal transduction, and found that Tpo induces phosphorylation of adapter molecules. Shc and Vav, and of serine/threonine kinases Raf-1 and mitogen-activated protein (MAP) kinases. Further, Tpo induced activation of Ras, MAP kinase kinase, MAP kinase and Pim-1. Taken together with other observations, we concluded that Tpo induces the activation of at least two distinct signaling pathways, a specific Tyk2-JAK2/STAT1-STAT3-STAT5 signaling cascade and a common Shc/Vav/Ras/Raf-1/MAP kinase kinase/MAP kinase signaling cascade.
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PMID:Thrombopoietin induces activation of at least two distinct signaling pathways. 854 84

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


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