Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of pituitary and extrapituitary prolactin include cellular proliferation and differentiation. PC12 cells was used as a model to delineate respective signaling of prolactin. Prolactin acted as a mitogen for undifferentiated PC12 cells, as measured by significant increases in bromodeoxyuridine incorporation and in cell numbers, with an efficacy equal to epidermal growth factor. Both the long and short form of the prolactin receptor was expressed, yet only the long isoform was tyrosine-phosphorylated upon agonist binding. Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1, -3, and -5a. Surprisingly, prolactin stimulated a sustained activation of Raf-B, without activation of the MAP kinases ERK1 or -2. Instead, in solid phase kinase assays using a glutathione S-transferase-c-Jun fusion protein (amino acids 1-79) as the substrate, a significant activation of the mitogen-activated protein Janus kinase (c-Jun N-terminal kinase; JNK) was observed. The prolactin-induced activation of JNK was prolonged and accompanied by a significant increase in c-Jun mRNA abundance and c-Jun protein synthesis. Moreover, analysis of bromodeoxyuridine incorporation at the single cell level revealed that epidermal growth factor-dependent incorporation was inhibited by PD98059 and independent of SB203580, whereas prolactin-induced incorporation was ERK and mitogen-activated protein kinase p38 independent but was abolished with JNK inhibition by 30 microm SB203580. Our studies suggest that prolactin may have a role in the growth of PC12 cells, where it stimulates concurrent mitogenic and differentiation-promoting signaling pathways.
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PMID:Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. 1080 11

CGP 57148 is a potent inhibitor of the ABL protein tyrosine kinase and a promising new compound for the treatment of a variety of BCR-ABL-positive leukemias. We used this enzyme inhibitor to characterize the biological effects of BCR-ABL in primary cells and two growth factor-dependent BCR-ABL-transfected cell lines. The effect of CGP 57148 on primary cells is dependent on the stage of differentiation. The growth of maturing chronic myeloid leukemia cells is independent of BCR-ABL in the presence of growth factors. However, the proliferation of leukemic immature cobblestone-forming area cells is almost completely blocked after the inhibition of the BCR-ABL kinase. In the BCR-ABL-transfected cell lines, M07/ p210 and Ba/F3/p185, CGP 57148 induces apoptosis by releasing cytochrome c, activating caspase 3, and cleavage of PARP. No alteration of the expression level of the apoptosis regulator BCL-2 was observed. In contrast, BCL-X was down-regulated after exposure to CGP 57148. Inhibitors of signal transduction proteins such as PI-3 kinase, mitogen-activated protein/extracellular signal-regulated kinase kinase, and Janus-activated kinase 2 pathways were not capable of a comparable down-regulation of BCL-X. The Fas/Fas ligand system was not involved either in the induction of apoptosis by CGP 57148. We conclude that the inhibition of the BCR-ABL kinase by CGP 57148 (a) preferentially inhibits the growth of immature leukemic precursor cells, (b) efficiently reverts the antiapoptotic effects of BCR-ABL by down-regulation of BCL-X, and (c) is more effective than the inhibition of the downstream signal transduction pathways of PI-3 kinase, mitogen-activated protein/extracellular signal-regulated kinase kinase, and Janus-activated kinase 2.
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PMID:The tyrosine kinase inhibitor CGP 57148 (ST1 571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X. 1081 21

Adipogenesis corresponds to the recruitment of new adipocytes in adipose tissue, and results from the proliferation/differentiation of preadipocytes. Production of paracrine and autocrine factors by adipocytes plays an important role in adipogenesis. We recently demonstrated the existence of adipocyte production of lysophosphatidic acid (LPA) both in vitro and in situ. This production is modulated by catecholamines via alpha 2-adrenergic receptors. Adipocyte-LPA present in conditioned media increases the growth of a preadipose cell line in culture. This growth is associated with an activation of mitogen-activated protein kinases, and of the focal adhesion kinase. Because of the close proximity of preadipocytes and adipocytes within adipose tissue, adipocyte-LPA could play an important role in autocrine/paracrine control of adipogenesis.
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PMID:LPA as a paracrine mediator of adipocyte growth and function. 1081 51

The mechanism by which Ang II stimulates the growth of vascular smooth muscle cells was investigated by measuring the phosphorylation of mitogen-activated protein kinases ERK 1 and ERK 2. Ca2+ ionophore was found to have effects practically analogous to Ang II. We found that the signaling pathway involves the activation of epidermal growth factor receptor (EGFR) kinase, activation of the adaptor proteins Shc and Grb2, and the small G-protein Ras. Although the mechanism of AT1- (or Ca2+)-induced activation of EGFR is not yet clear, we have found that calcium-dependent protein kinase CAKss/PYK2 and c-Src are involved in this process. These studies indicate a transactivation mechanism that utilizes EGFR as a bridge between a Gq-coupled receptor and activation of phosphotyrosine generation.
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PMID:Angiotensin II-mediated vascular smooth muscle cell growth signaling. 1082 89

We analyzed the expression of IL-12Rbeta1 and IL-12Rbeta2 and the role of IL-12 in the activation of monocyte-derived dendritic cells (DCs) via IL-12Rbeta1-mediated signaling events. Flow cytometric analysis revealed that IL-12Rbeta1 was expressed in T cells, Con A blasts, and monocyte-derived DCs, but not in monocytes, while its transcript was detected in all of these cell types. Transcriptional expression of IL-12Rbeta2 was observed in T cells, Con A blasts, and monocyte-derived DCs, but not monocytes. The ligation of DCs as well as Con A blasts by IL-12 induced the production of GM-CSF, IL-1beta, IL-6, TNF-alpha, and IFN-gamma at the transcription levels. Furthermore, stimulation of DCs with IL-12 induced IL-12p40 transcript, but not IL-12p35 transcript, whereas this stimulation caused the expressions of both transcripts in Con A blasts. Stimulation of DCs with IL-12 caused a tyrosine phosphorylation of several intracellular proteins, and the pattern of these events were distinct from those of IL-12-stimulated Con A blasts. IL-12 also induced tyrosine phosphorylation of IL-12Rbeta1 as well as recruitment of several tyrosine-phosphorylated proteins to IL-12Rbeta1 in DCs and Con A blasts. Receptor engagement of DCs as well as Con A blasts by IL-12 resulted in activation of Janus kinase 2 and Tyk2 kinases and Stat3 and Stat4 transcription factors and the association of these proteins to IL-12Rbeta1. Stimulation with IL-12 caused a tyrosine phosphorylation and enzymatic activity of a family of mitogen-activated protein kinases, p38mapk. These results suggest that IL-12 acts directly on DCs to induce their functional activation via IL-12Rbeta1-mediated signaling events.
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PMID:IL-12 responsiveness and expression of IL-12 receptor in human peripheral blood monocyte-derived dendritic cells. 1086 Oct 35

The interaction of BAD (Bcl-2/Bcl-X(L)-antagonist, causing cell death) with Bcl-2/Bcl-X(L) is thought to neutralize the anti-apoptotic effects of the latter proteins, and may represent one of the mechanisms by which BAD promotes apoptosis. A variety of survival signals are reported to induce the phosphorylation of BAD at Ser(112) or Ser(136), triggering its dissociation from Bcl-2/Bcl-X(L). Ser(136) is thought to be phosphorylated by protein kinase B (PKB, also called Akt), which is activated when cells are exposed to agonists that stimulate phosphatidylinositol 3-kinase (PI3K). In contrast, Ser(112) is reported to be phosphorylated by mitogen-activated protein (MAP) kinase-activated protein kinase-1 (MAPKAP-K1, also called RSK) and by cAMP-dependent protein kinase (PKA). Here we identify Ser(155) as a third phosphorylation site on BAD. We find that Ser(155) is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser(155) prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins. We also provide further evidence that MAPKAP-K1 mediates the phosphorylation of Ser(112) in response to agonists that activate the classical MAP kinase pathway. However insulin-like growth factor 1, a potent activator of PI3K and PKB does not increase the phosphorylation of Ser(136) in BAD-transfected HEK-293 cells, and nor is the basal level of Ser(136) phosphorylation suppressed by inhibitors of PI3K.
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PMID:Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Ser155. 1088 Mar 54

Activation of human eosinophils by platelet-activating factor (PAF) involves multiple signal transduction pathways. Among these, protein kinase C has been demonstrated both to mediate respiratory burst and to suppress an alternative pathway of activation of respiratory burst and arachidonic acid metabolism in eosinophils. We utilized inhibitors of protein tyrosine kinases (PTK) to elucidate the role of PTK in PAF-induced activation of eosinophils. Eosinophils were isolated from peripheral blood of atopic donors and stimulated with PAF in the absence or presence of broad-spectrum PTK inhibitors-genistein or lavendustin A; an inhibitor of mitogen-activated protein (MAP) kinase activation-tyrphostin AG126; or an inhibitor of Janus kinase 2 (Jak2)-tyrphostin B42 (AG490). PAF induced superoxide anion (O2-*) generation, leukotriene C4 (LTC4) release, intracellular calcium ion mobilization and tyrosine phosphorylation of multiple eosinophil proteins in a concentration-dependent manner. All of these responses were concentration-dependently inhibited by genistein; lavendustin A also exhibited potent inhibition of PAF-induced LTC4 release. AG126 had no effect on either O2-* generation or LTC4 release, while AG490 inhibited both responses, albeit less effectively than genistein. We conclude that PAF activates PTK in human eosinophils and that this signalling pathway is involved in eliciting respiratory burst and leukotriene production. The specific PTK(s) involved are unknown but may include Jak2.
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PMID:Involvement of protein tyrosine kinases in activation of human eosinophils by platelet-activating factor. 1088

The Akt/PKB protein kinase is implicated in the control of cell cycle progression and the suppression of apoptosis in cancer cells. Here we describe the use of a conditionally active form of Akt/PKB (M+ Akt:ER*) to study the ability of this protein to influence biological processes that are central to the process of oncogenic transformation of mammalian cells. Activation of M+ Akt:ER* in Rat1 cells elicited alterations in cell morphology and promoted anchorage-independent growth in agarose with high efficiency. Consistent with these observations, activation of M+ Akt:ER* suppressed the apoptosis of Rat1 cells that occurs after the detachment of these cells from extracellular matrix. Furthermore, activation of M+ Akt:ER* was sufficient to promote the progression of quiescent Rat1 cells into the S and G2-M phases of the cell cycle. In accord with this is the observation that activation of M+ Akt:ER* led to decreased expression of the cyclin-dependent kinase inhibitor p27Kip1 with a concomitant increase in cyclin-dependent kinase-2 activity. Perhaps surprisingly, activation of M+ Akt:ER* or expression of a constitutively active form of Akt led to rapid activation of MAP/ERK Kinase (MEK) and the extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinases in Rat1 cells. However, pharmacological inhibition of MEK by PD098059 did not inhibit the morphological alterations of Rat1 cells that occur after M+ Akt:ER* activation. These data suggest that M+ Akt:ER* can activate a number of pathways in Rat1 cells, leading to significant alterations in a number of biological processes. The conditional transformation system described here will allow further elucidation of the ability of Akt to contribute to both the normal response of cells to mitogenic stimulation and the aberrant proliferation observed in cancer cells.
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PMID:Oncogenic transformation of cells by a conditionally active form of the protein kinase Akt/PKB. 1091 95

Protein kinase A (PKA) plays an essential role in the depolarization-induced c-fos expression in PC12 cells although the exact mechanism is unknown. Here we demonstrate that PKA is required for depolarization-induced activation of both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinase in PC12 cells. In addition, we have found that the depolarization-induced tyrosine phosphorylation of proline-rich tyrosine kinase (PYK) 2, a key calcium-sensitive upstream mediator of MAP kinase activation, is profoundly blocked by PKA inhibition. In contrast to the depolarization-induced signaling, the ERK and PYK2 activation by bradykinin (1 microM), a G-protein coupled receptor agonist, was not blocked by PKA inhibition. These findings suggest that PKA inhibition prevents depolarization-induced PYK2/MAP kinase pathway activation, thereby inhibiting the early gene expression.
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PMID:Protein kinase A activity is required for depolarization-induced proline-rich tyrosine kinase 2 and mitogen-activated protein kinase activation in PC12 cells. 1092 66

Transforming growth factor beta (TGF-beta)-mediated apoptosis is one of the major death processes in the liver. We have previously shown that epidermal growth factor (EGF) is an important survival signal for TGF-beta-induced apoptosis in fetal hepatocytes (Fabregat et al., FEBS Lett 1996;384:14-18). In this work we have studied the intracellular signaling implicated in the protective effect of EGF. We show here that EGF activates p42 and p44 mitogen-activated protein kinases (MAPK). However, mitogen extracellular kinase (MEK) inhibitors do not block the survival effect of EGF. EGF also activates phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB/AKT) in these cells. The presence of PI 3-kinase inhibitors blocks the protective effect of EGF on cell viability, DNA fragmentation, and caspase-3 activity. We have found that TGF-beta disrupts the mitochondrial transmembrane potential (DeltaPsi(m))( )and activates the release of cytochrome c, this effect being blocked by EGF, via a PI 3-kinase-dependent pathway. A detailed study on bcl-2 superfamily gene expression shows that TGF-beta produces a decrease in the messenger RNA (mRNA) and protein levels of bcl-x(L), an antiapoptotic member of this family, capable of preventing cytochrome c release. EGF is able to maintain bcl-x(L) levels even in the presence of TGF-beta. PI 3-kinase inhibitors completely block the protective effect of EGF on TGF-beta-induced bcl-x(L )down-regulation. We conclude that PI 3-kinase mediates the survival effect of EGF on TGF-beta-induced death by acting upstream from the mitochondrial changes, i.e., preventing bcl-x(L) down-regulation, cytochrome c release, and activation of caspase-3.
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PMID:Epidermal growth factor impairs the cytochrome C/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway. 1096 Apr 45


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