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 mechanisms that restrict cell proliferation play an important regulatory role in differentiation and tumorigenesis. The growth of PRL-secreting cells of the anterior pituitary is known to be highly estrogen dependent; however, estrogen may act indirectly via growth regulatory polypeptides. We have used the GH4C1 rat pituitary cell line to investigate the action of two classes of growth regulatory polypeptides, transforming growth factor-alpha (TGF alpha) and TGF beta. TGF alpha and TGF beta each inhibit GH4 cell proliferation, as measured by cell number and [3H]thymidine incorporation, and given together arrest GH4 cell proliferation. The growth inhibitory action of TGF alpha is concentration dependent (IC50 = 100 pM) and saturable. Activin-A, a TGF beta-related polypeptide, also inhibits proliferation, but is less effective than TGF beta. TGF alpha and TGF beta each alter GH4 cell cycle distribution by decreasing in the percentage of S phase cells (74% and 34%, respectively) and increasing proportionally G0-G1 phase cells. The growth inhibitory action of TGF alpha differs from that of TGF beta in that TGF alpha also causes a temporary accumulation of cells in G2-M phases. We next initiated experiments to evaluate the role of protein kinase-C in the growth inhibitory actions of TGF alpha and TGF beta. The alpha- and beta-isoforms of protein kinase-C were down-regulated by pretreatment with 12-O-tetradecanoylphorbol-13-acetate, yet TGF alpha and TGF beta still substantially inhibited GH4 cell proliferation. We next compared the actions of TGF alpha and TGF beta on two other well characterized prolonged GH4 responses. TGF alpha and TGF beta each increased GH4 cell adhesion, but differed in their effects on PRL production. This indicates that TGF alpha and TGF beta activate different signaling pathways in GH4 cells. Activin-A acted like TGF beta by enhancing cell-substratum adhesion and inhibiting PRL production, consistent with an interaction at a common receptor site. Taken together these results identify biological functions for TGF alpha, TGF beta, and activin-A on PRL cells and open the possibility that they may represent the direct in vivo mediators of estrogen action to regulate the growth of PRL cells in the anterior pituitary gland.
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PMID:Transforming growth factor-alpha and -beta are potent and effective inhibitors of GH4 pituitary tumor cell proliferation. 200 14

The acquisition of FSH receptor during preantral folliculogenesis is believed to be a key step in the subsequent development of follicles. We examined the interaction between activin and cAMP in FSH receptor induction in rat granulosa cells by measuring 125I-FSH binding and FSH receptor mRNA. In the 125I-FSH binding study, 0.2 mM 8-Br-cAMP and 1 microM forskolin were maximally effective in FSH receptor induction (169 and 220% respectively of control), while higher concentrations gave attenuated responses. It appears that cAMP has ambivalent effects on FSH receptor induction depending on the concentration and length of exposure. Activin alone dramatically increased the number of FSH receptors (314% of control). Moreover, synergistic effects of activin and 8-Br-cAMP or forskolin were observed on FSH receptor induction: a combination of activin (80 ng/ml) and low doses of 8-Br-cAMP (0.2 mM) or forskolin (1 microM) was most effective (160 or 140% of that induced by activin alone) and receptor levels reached a maximum at 24 h. These levels than markedly decreased after 72 h of incubation. Northern blot analysis revealed that the combination of activin (80 ng/ml) and 8-Br-cAMP (0.2 mM) or forskolin (1 microM) increased FSH receptor mRNA to about 140% of that induced by activin alone. These results indicate that activin and cAMP induced FSH receptor synergistically. However, activin did not enhance the production of cAMP induced by forskolin. In addition, a protein kinase A inhibitor (H89) (2 microM), which inhibited the effects of forskolin, had no effect on the action of activin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction between activin A and cAMP in the induction of FSH receptor in cultured rat granulosa cells. 749 May 22

Isolated explants from the animal hemisphere of Xenopus embryos were incubated with Xenopus basic fibroblast growth factor (XbFGF) or human activin A. XbFGF incubation resulted in the rapid activation of mitogen-activated protein kinase (MAPK) and ribosomal S6 protein kinase (pp90rsk) in a dose-dependent manner with the highest levels of activation occurring at 50 ng/ml. Maximal activation occurred within 6-10 min after the addition of growth factor, and the activity of both kinases declined to unstimulated levels after 30 min. Activin was unable to activate either MAPK or pp90rsk in the Xenopus explants to a substantial level, although it induced dorsal mesoderm better than XbFGF under the same experimental conditions. The regulatory protein Xwnt-8 did not activate MAPK, nor did it enhance the activation of MAPK by XbFGF. XbFGF was able to activate MAPK through at least the midgastrula stage, suggesting that this family of growth factors may have a role in gastrula-stage events.
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PMID:Fibroblast growth factor, but not activin, is a potent activator of mitogen-activated protein kinase in Xenopus explants. 751 Apr 4

Activin, a member of the transforming growth factor-beta superfamily, binds to two classes of cell surface receptors. These receptors, designated type I and type II, are structurally related members of transmembrane serine kinase superfamily. Antibodies specific for either type I or type II activin receptor can coprecipitate complexes containing both affinity-labeled receptors from activin-responsive cells. Two type I receptors show cell-specific expression and associate with the ligand-binding, type II receptors. To investigate the roles of the cytoplasmic receptor domains in signaling through a heteromeric ligand receptor complex, we have made kinase-deficient activin receptors and correlated their losses in kinase activity with inhibitory effects on an activin-dependent transcriptional response in activin-responsive cell lines. Wild-type activin type II receptors phosphorylate activin type I receptors in transfected COS cells. In contrast, kinase-deficient activin type II receptors fail to phosphorylate type I receptors in transfected COS cells and act as dominant negative mutants to block activin-induced transcriptional activity in both Chinese hamster ovary and K562 (human erythroleukemia) cells. Kinase-deficient activin type IB receptors also block activin-induced transcriptional activity in both Chinese hamster ovary and K562 cells, whereas kinase-deficient activin type I receptors have no effect in either cell line. These results indicate that kinase activities of both type II and type I receptors are required for activin signaling, and that the two type I receptors, which are expressed in a tissue-specific manner, are functionally distinct.
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PMID:Inactivation of activin-dependent transcription by kinase-deficient activin receptors. 758

Animal cap explants from Xenopus embryos injected with a dominant negative Raf-1 mutant, termed NAF (not a functional Raf), demonstrated a complete block to basic fibroblast growth factor (FGF)-stimulated mesoderm induction. Activin induction of mesoderm was normal in embryos that expressed NAF. Injection of NAF RNA into 2-cell stage embryos blocked normal development during neurula stages and caused severe posterior truncations in tadpoles. The phenotype induced by NAF could be rescued by coinjection of wild-type raf-1 RNA. The NAF mutant functioned by specifically blocking the activation of endogenous Raf kinase activity. These findings suggest that Raf-1 mediates FGF, but not activin, receptor signaling during mesoderm induction and implicate Raf-1 as a key signaling molecule in the development of posterior structure.
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PMID:Raf-1 kinase is essential for early Xenopus development and mediates the induction of mesoderm by FGF. 768 75

Activin type II receptors are transmembrane protein-serine/threonine kinases. By using a reverse-transcription PCR assay to screen for protein kinase sequences, we isolated a cDNA clone, activin X1 receptor, from rat brain that encodes a 55-kDa transmembrane protein-serine kinase which is structurally related to other receptors in this kinase subfamily. The predicted protein consists of 509 amino acids, and the kinase domain shows 40% and 37% identity to the activin and transforming growth factor beta type II receptors, respectively. No activin-binding was observed when activin X1 receptor was expressed alone in COS-M6 cells; however, coexpression with type II activin receptors gave rise to a 68-kDa affinity-labeled complex in addition to the 85-kDa type II receptor complex. The size of this cross-linked band is consistent with the size of the type I activin receptor; furthermore, activin X1 receptor associated with type II receptors, as judged by coimmunoprecipitation with type II receptor antibodies. These data suggest that activin X1 receptor can serve as an activin type I receptor and that the diverse biological effects of activins may be mediated by a complex formed by the interaction of two transmembrane protein-serine kinases.
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PMID:Cloning and characterization of a transmembrane serine kinase that acts as an activin type I receptor. 824 34

Follistatins, activins, and inhibins are expressed in a wide range of tissues where they function as autocrine and/or paracrine factors. Activin B (beta B beta B) and inhibin B (alpha beta B) are the predominant forms expressed in the rat anterior pituitary. This study was designed to evaluate the regulation of the messenger RNAs (mRNAs) for inhibin alpha and beta B, and follistatin, relative to each other, using cultured rat anterior pituitary cells. Activin A stimulated follistatin (a maximal 4-fold stimulation by 6 h) and beta B (a maximal 1.7-fold stimulation after 2 h) mRNA levels. Although inhibin A dramatically decreased follistatin mRNA levels (34% of the control value after 24 h), it only marginally affected those of beta B (86% of the control value after 2 h). Follistatin inhibited the accumulation of its own mRNA (46% of the control value after 6 h), but had no statistically significant effect on beta B or alpha mRNA levels. Inhibin A was the only treatment that had an effect on alpha mRNA levels, causing a slight decrease (82% of the control value by 24 h). The effects of activin A and inhibin A on follistatin and beta B mRNA levels were dose dependent. Moreover, follistatin and inhibin A blocked the effects of activin A. Immunoneutralization experiments were performed to determine whether locally secreted activin B regulates the expression of these three mRNAs. A monoclonal antibody to activin B reduced follistatin and beta B mRNA levels (37% and 73% of the control value, respectively) and enhanced the stimulatory effect of exogenous activin A on these mRNAs (840% vs. 300% and 170% vs. 145% of the control value, respectively); there was no change in alpha mRNA accumulation. GnRH and activators of the protein kinase A (forskolin) and protein kinase C (12-O-tetradecanoylphorbol acetate) pathways also had differential effects on follistatin, beta B, and alpha mRNA levels. GnRH stimulated follistatin mRNA levels, but suppressed those of beta B. 12-O-Tetraphorbol acetate had no effect on beta B, but stimulated follistatin mRNA levels to the same extent as forskolin. Of these agents, only forskolin produced a marginal inhibitory effect on alpha mRNA accumulation. Testosterone decreased both follistatin and beta B mRNA levels without affecting those of alpha. The results of this study demonstrate that the local production of rat anterior pituitary follistatin, activin B, and inhibin B is regulated by hypothalamic, peripheral, and local factors in such a way that the ratios between activin B and its two inactivators, follistatin and inhibin B, are very tightly maintained.
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PMID:Pituitary follistatin and inhibin subunit messenger ribonucleic acid levels are differentially regulated by local and hormonal factors. 882 87

Transforming growth factor-beta (TGF-beta) and activin-A, two members of a ubiquitous family of regulators of growth, differentiation and hormonogenesis, are produced by the human placenta. Their effects on placental hCG, inhibin, and oestrogen production in vitro, either alone or in combination, were investigated using cultured Percoll-purified placental trophoblasts. Inhibin and hCG were measured by immunoassay, while aromatase activity (i.e. oestrogen production) was measured using the tritiated water method. Aromatase activity and production of hCG, but not inhibin, were inhibited (up to approximately 30 per cent) in a dose-dependent fashion by 48 h treatment with TGF-beta. The effects were significant at all doses tested, from 0.1-10 ng/ml. In contrast, activin stimulated hCG production and aromatase activity over the doses tested (0.25-25 ng/ml). The maximum effect (approximately 50 per cent stimulation above control) was seen at the 2.5 ng/ml dose, with lesser effects seen at the lower and higher doses. This characteristic bell-shaped dose-response curve was maintained in the presence of TGF-beta (10 ng/ml) or a maximally-effective dose of forskolin (6.7 microM). This suggests that the actions of activin were independent of those of TGF-beta, and were not mediated by the protein kinase-A pathway. Activin had a weak stimulatory effect on inhibin production. The results indicate that in the placenta activin and TGF-beta have opposing actions on hormonogenesis. Both factors may play a role in regulating placental function and the timing and progression of labour.
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PMID:Activin-A stimulates, while transforming growth factor beta 1 inhibits, chorionic gonadotrophin production and aromatase activity in cultured human placental trophoblasts. 891 9

The aims of this study were to apply enzyme-linked immunosorbent assays (ELISA) for human follistatins (FS) to measure total immunoreactive (ir-) rat FS and free rat FS, and investigate the regulation of production of total ir-FS and free FS by rat granulosa cells (GC) in vitro. Production of ir-inhibin was monitored as an index of GC function. The ELISAs for total ir-FS, based on an immunoradiometric assay developed recently for human FS, and free FS, based on capture of FS by a monoclonal antibody and detection by activin A binding, had sensitivities of 0.4 and 0.8 ng recombinant human (rh-) FS 288/ml, respectively, and did not cross-react with inhibin A, rLH, or FSH. rh-Activin did not cross react in the total ir-FS ELISA, but interfered with the measurement of free FS. Dilutions of GC-conditioned medium were parallel to the standard curve of rh-FS 288 for each assay. The values obtained in the free FS assay were 10- to 20-fold higher than those in the total ir-FS ELISA, suggesting that rat FS may be recognized by the antibodies differently than the human standard. Both total ir-FS and free FS production by undifferentiated GC from diethylstilbestrol (DES)-treated, immature rats increased with cell number and time in culture and were stimulated dose dependently by FSH, rh-activin A (except free FS, which was not measured because of interference), forskolin, and phorbol 12-myristrate. The effects of FSH and activin on FS production by undifferentiated GC were additive. There were significant effects of degree of differentiation of GC on basal FS production and responsiveness to FSH, LH, and rh-activin A. Both total ir-FS and free basal FS production increased up to 4-fold with the degree of differentiation of GC, produced by treating rats in vivo with DES (undifferentiated), DES plus FSH (partially differentiated), or DES plus FSH plus hCG (fully differentiated). The addition of FSH in vitro increased FS production by undifferentiated and partially differentiated GC, but not by fully differentiated GC. The only detectable effect of LH on FS production was on partially differentiated GC. Activin A stimulated total ir-FS production by undifferentiated and partially differentiated GC, but inhibited total ir-FS production by fully differentiated GC. Ir-inhibin production in these experiments was similar to that of FS with the following exceptions; phorbol 12-myristrate inhibited ir-inhibin production by undifferentiated GC, basal ir-inhibin decreased in fully differentiated GC, FSH stimulated ir-inhibin only in undifferentiated GC, and rh-activin A stimulated ir-inhibin at all stages. It is concluded that 1) FS protein production by cultured undifferentiated rat GC is up-regulated by FSH and activin, possibly via both protein kinase A and C pathways; 2) increasing GC differentiation is associated with a significant increase in basal FS production by rat GC and a change in the hormonal regulation of FS production; and 3) FS and ir-inhibin production by cultured rat GC can be differentially regulated. The results are consistent with the hypothesis that activin tone decreases within follicles as they develop due to increased production of the activin-binding protein FS.
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PMID:Regulation of follistatin production by rat granulosa cells in vitro. 916 47

Cytokines are growth inhibitory in a target cell specific manner. The signaling pathways that characterize each cell type play a crucial role in determining the responsiveness to cytokine triggering. Activin A has been shown to suppress the growth of primary hepatocytes. Similarly, the human HepG2 hepatoma cell line was growth arrested by activin A as judged by lack of cell proliferation and suppression of DNA synthesis. In HepG2 cells activin A further induced accumulation of retinoblastoma protein in the hypophosphorylated form known to prevent entrance into S phase. This finding implies the involvement of cyclin dependent kinases and CDK inhibitors. Examination of HepG2 cells following addition of activin A revealed reduced expression of CDK4 and conversely, an increase in the CKI p21(WAF1/Cip1). This accumulation of p21(WAF1/Cip1) protein was partly due to increased transcriptional activity. Functional inactivation of p53, using a miniprotein that oligomerizes with p53 and abrogates DNA binding, abolished the ability of activin A to induce transcriptional activation from the p21(WAF1/Cip1) promoter. Thus, activin A, like transforming growth factor beta, seems to suppress cell growth through the downstream target Rb. However, each of these cytokines seem to operate through a distinct pathway.
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PMID:Involvement of p21(WAF1/Cip1), CDK4 and Rb in activin A mediated signaling leading to hepatoma cell growth inhibition. 934 4


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