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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular smooth muscle cells (SMCs) occur throughout the vascular tree and have important physiological functions. They are also involved in pathological processes such as development and progression of atherosclerotic lesions, restenosis following angioplasty, and in hypertension. This review is focused on the role of the insulin-like growth factor (IGF) system in proliferation, migration, and hypertrophy of vascular SMCs and its interaction with insulin and other growth factors. The IGF-I receptor is highly expressed in SMCs in intact arteries and in cultured SMCs and is activated by binding of IGF-I to the two alpha-subunits. Insulin and IGF-II from the circulation can interact with the IGF-I receptor at higher concentrations. Insulin receptors are few or absent in SMCs and circulating insulin concentrations in vivo are probably too low for a direct action of insulin on the IGF-I receptor in SMCs. Receptor activation initiates a number of signal transduction pathways. Increased phosphatidylinositol turnover and calcium mobilization correlates with actin filament reorganization and stimulation of directed migration of the SMC in a gradient of IGF-I. The effects of IGF-I receptor activation on signal transduction pathways (eg, the MAP kinase cascade) implicated in DNA synthesis and proliferation are weak and this correlates with the meager mitogenic activity of IGF-I in SMC. Several components of the IGF-system in SMC are regulated by growth factors such as platelet-derived growth factor (PDGF)-BB and basic fibroblast growth factor (bFGF).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The insulin-like growth factor system in vascular smooth muscle: interaction with insulin and growth factors. 747 13

Directed migration or chemotaxis of arterial smooth muscle cells (SMC) contributes to intimal SMC accumulation, a key event in the development of atherosclerotic lesions and in restenosis after angioplasty. The present study compares and contrasts insulin-like growth factor I (IGF-I) and platelet-derived growth factor (PDGF-BB) as chemoattractants and mitogens for human arterial SMC. Compared with PDGF-BB, IGF-I is a weaker SMC mitogen. Thus, PDGF-BB, but not IGF-I, evokes a strong and rapid activation of mitogen-activated protein (MAP) kinase kinase and MAP kinase. However, IGF-I is a potent stimulator of directed migration of human arterial SMC, as measured in a Boyden chamber assay. The half-maximal concentration for migration is similar to the Kd for IGF-I receptor interaction. An IGF-I receptor-blocking antibody blocks the effects of IGF-I, IGF-II, and insulin, indicating that the effects are indeed mediated through the IGF-I receptor. The maximal effect of IGF-I on directed migration ranges between 50% and 100% of the effect of PDGF-BB, the strongest known chemoattractant for SMC. The ability of IGF-I and PDGF-BB to induce chemotaxis coincides with their ability to stimulate phosphatidylinositol turnover, diacylglycerol formation, and intracellular Ca2+ flux and suggests that these signaling pathways, but not activation of the MAP kinase cascade, are required for chemotaxis of human arterial SMC.
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PMID:Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation. 813 65

Evidence has accumulated that suggests that insulin-like growth factors (IGFs) exert a positive influence on myoblast differentiation. We have undertaken to study the signalling events required for differentiation resulting from type-1 IGF receptor stimulation in C2 myoblasts, where autocrine production of IGF-II was abolished by means of antisense RNA. Exposure of the cells to IGFs leads to a rapid and sustained activation of phosphatidyl-inositol 3-kinase followed by the expression of Myod, myogenin and differentiation. The fungal metabolite, wortmannin, inhibits both PI 3-kinase and muscle differentiation with an IC 50 in the nanomolar range. IGFs are also known to cause a rapid activation of MAP kinase. However, the synthetic inhibitor of MEK, PD098059, which prevents MAP kinase activation, does not affect myoblast differentiation. These results provide evidence that PI 3-kinase, but not MAP kinase, is required for insulin-like growth factor receptor-dependent differentiation of muscle cells.
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PMID:Wortmannin inhibits IGF-dependent differentiation in the mouse myogenic cell line C2. 923 22

The biological actions of the insulin-like growth factors IGF-I and IGF-II are mediated by their activation of the IGF-IR, a transmembrane tyrosine kinase linked to the ras-raf-MAPK cascade. Functional IGF-IRs are required for the cell to progress through the cell cycle. Most importantly, cells lacking this receptor cannot be transformed by any of a number of dominant oncogenes, a finding that proves that the presence of the IGF-IR is important for the development of a malignant phenotype. Consistent with this role, the IGF-IR displays a potent antiapoptotic effect, both in vitro and in vivo. Because of its key role in the transformation process, the IGF-IR is actively studied as a potential therapeutic target in different types of neoplastic growth.
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PMID:The insulin-like growth factor-I receptor signaling pathways are important for tumorigenesis and inhibition of apoptosis. 951 87

We have previously shown that the insulin-like growth factors (IGFs) stimulate both proliferation and differentiation of skeletal muscle cells in culture, and that these actions in L6A1 muscle cells may be modulated by three secreted IGF binding proteins (IGFBPs), IGFBP-4, -5, and -6. Since we found that the temporal expression pattern of IGFBP-4 and IGFBP-5 differed dramatically during the transition from proliferating myoblasts to differentiated myotubes, we undertook the current study to examine the effects of purified IGFBP-4 and IGFBP-5 on IGF-stimulated actions in L6A1 muscle cells. As has been shown for other cell types, we found that IGFBP-4 had only inhibitory actions, inhibiting IGF-I and IGF-II-stimulated proliferation and differentiation. In contrast, IGFBP-5 exhibited both inhibitory and stimulatory actions. When added in the presence of 30 ng/ml IGF-I, IGFBP-5 (250 ng/ml) inhibited all markers of the early proliferative response: the tyrosine phosphorylation of the cytoplasmic signaling molecules IRS-1 and Shc, the activation of the MAP kinases, ERK1 and 2, the elevation of c-fos mRNA, the early inhibition of the elevation in myogenin mRNA, and the increase in cell number. In contrast, IGFBP-5 stimulated all aspects of the myogenic response to IGF-I: the later rise in myogenin mRNA, the elevation of creatine kinase activity, and the fusion of myoblasts into myotubes. This dual response to IGFBP-5 was greatest when it was added at a molar ratio of IGFBP-5 to IGF-I of 2:1. In contrast, when IGFBP-5 was added in the presence of IGF-II, it inhibited both proliferation and differentiation. Neither IGFBP had any effect when added in the presence of R3 IGF-I, an analog with substantially reduced affinity for IGFBPs. Our results suggest that the role of IGFBP-4 is mainly to sequester excess IGFs, and thus inhibit all actions. IGFBP-5, however, is capable of eliciting a dual response, possibly due to its unique ability to associate with the cell membrane.
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PMID:Modulation of insulin-like growth factor actions in L6A1 myoblasts by insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5: a dual role for IGFBP-5. 973 44

The avian granulosa cells proliferate during follicular growth phase and differentiate to produce progesterone in response to luteinizing hormone (LH) when the follicle becomes the largest. In order to study the involvement of mitogen-activated protein (MAP) kinase in proliferation of the granulosa cells in avian species, quail granulosa cells were cultured for 66 h with various hormones (follicle stimulating hormone (FSH), LH, progesterone, estradiol-17beta, testosterone), or growth factors (transforming growth factor alpha (TGF alpha), epidermal growth factor (EGF), insulin-like growth factor I (IGF-I), IGF-II), and the presence of immunodetectable MAP kinase was examined in the cell lysates. When the granulosa cells were cultured with TGF alpha, the cell number as well as the incorporation of [3H]thymidine was increased. Other hormones or growth factors caused no significant increase in cell numbers. Stimulation of the cells with TGF alpha for 10 min caused a retarded mobility of MAP kinase in the gel of SDS-PAGE. Both the increases in [3H]thymidine incorporation and the retarded mobility were inhibited by the presence of a tyrosine kinase inhibitor, genistein, indicating the importance of phosphorylation of protein during the TGF alpha-stimulation.
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PMID:Involvement of mitogen-activated protein kinase in transforming growth factor alpha-stimulated cell proliferation in the cultured granulosa cells of the Japanese quail. 1057 44

Skeletal myogenic cells respond to the insulin-like growth factors (IGF-I and IGF-II) by differentiating or proliferating, which are mutually exclusive pathways. What determines which of these responses to IGF skeletal myoblast undergo is unclear. IGF-binding protein-related protein 1 (IGFBP-rP1) is a secreted protein with close homology to the IGF-binding proteins (IGFBPs) in the N-terminal region. IGFBP-rP1, previously called mac25 and IGFBP-7, is highly expressed in C2 skeletal myoblasts during the proliferative phase, but is down-regulated during myoblast differentiation. To determine the role of IGFBP-rP1 in myogenesis, IGFBP-rP1 was overexpressed in C2 myoblasts using a retroviral vector. Western blots indicated that the resulting C2-rP1 myoblasts secreted approximately 27-fold higher levels of IGFBP-rP1 than control C2-LX myoblasts that were transduced with a control vector (LXSN). Compared with C2-LX myoblasts, the differentiation responses of C2-rP1 myoblasts to IGF-I, IGF-II, insulin, and des(1-3)IGF-I were significantly reduced (P < 0.05). However, proliferation responses of C2-rP1 and C2-LX myoblasts to these same factors were not significantly different. Exposure of control C2-LX myoblasts to factors secreted by C2-rP1 myoblasts using a transwell coculture system reduced C2-LX myoblast differentiation significantly (P < 0.05). Experiments with the mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 suggested that IGFBP-rP1 inhibits a MAPK-dependent differentiation pathway. In confirmation of this idea, levels of phosphorylated extracellular signal-regulated kinase-2 (a MAPK) were reduced in C2-rP1 myoblasts compared with those in C2-LX myoblasts. These findings indicate that IGFBP-rP1 may function as an autocrine/paracrine factor that specifies the proliferative response to the IGFs in myogenesis.
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PMID:Insulin-like growth factor (IGF)-binding protein-related protein-1: an autocrine/paracrine factor that inhibits skeletal myoblast differentiation but permits proliferation in response to IGF. 1061 28

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is a 28-kDa plasma protein that binds to IGF-I and IGF-II with high affinity. IGFBP-1 is elevated in the blood as a result of sepsis, AIDS, excessive alcohol consumption, and diabetes and may, in part, be responsible for the wasting observed during these pathophysiological conditions. The liver is the principal site of IGFBP-1 synthesis, and we have previously shown that proinflammatory cytokines can directly stimulate IGFBP-1 secretion in a human hepatoma cell line (HepG2). The purpose of the present study was to investigate the role of the MAP kinase pathway in regulating IGFBP-1 synthesis by IL-1beta. We show that IL-1beta stimulates the phosphorylation of ERK-1 and -2 in a time- and dose-dependent manner. In addition, the MAP kinase-kinase MEK-1 and the ribosomal S6-kinase RSK-1 are also phosphorylated in response to IL-1beta. The transcription factor CREB, a potential substrate of both protein kinase A (PKA) and RSK-1, is phosphorylated in response to IL-1beta and cAMP in HepG2 cells. The ability of IL-1beta to stimulate the expression of IGFBP-1 and the phosphorylation of the above kinases was specifically inhibited by PD98059, a MEK-1 inhibitor. cAMP also stimulated IGFBP-1 synthesis, but PD98059 failed to block the cAMP effect. Conversely, a PKA inhibitor (H-89) inhibited the ability of cAMP, but not IL-1beta to stimulate IGFBP-1 synthesis. The effect of IL-1beta and cAMP on IGFBP-1 messenger RNA (mRNA) accumulation was additive. IL-1beta, cAMP, PD98059, and H-89 had similar effects on the accumulation of IGFBP-1 protein and mRNA. IL-1beta and cAMP did not change the half-life of IGFBP-1 mRNA, but PD98059 and SB202190, a p38 MAP kinase inhibitor, destabilized IGFBP-1 mRNA and blocked the phosphorylation of RSK-1 in response to IL-1beta. Our data demonstrate that the MAP kinase signal transduction pathway plays an important role in the regulation of IGFBP-1 synthesis by IL-1beta.
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PMID:Stimulation of insulin-like growth factor binding protein-1 synthesis by interleukin-1beta: requirement of the mitogen-activated protein kinase pathway. 1096 86

Insulin-like growth factor (IGF)-I and -II have been cloned from a number of teleost species, but their cellular actions in fish are poorly defined. In this study, we show that both IGF-I and -II stimulated zebrafish embryonic cell proliferation and DNA synthesis in a concentration-dependent manner, whereas insulin had little mitogenic activity. Affinity cross-linking and immunoblotting studies revealed the presence of IGF receptors with the characteristics of the mammalian type I IGF receptor. Competitive binding assay results indicated that the binding affinities of the zebrafish IGF-I receptors to IGF-I, IGF-II, and insulin are 1.9, 2.6, and >190 nM, indicating that IGF-I and -II bind to the IGF-I receptor(s) with approximately equal high affinity. To further investigate the cellular mechanism of IGF actions, we have studied the effects of IGFs on two major signal transduction pathways: mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3 kinase). IGFs activated MAPK in zebrafish embryonic cells in a dose-dependent manner. This activation occurred within 5 min of IGF-I stimulation and disappeared after 1 h. IGF-I also caused a concentration-dependent activation of protein kinase B, a downstream target of PI3 kinase, this activation being sustained for several hours. Inhibition of MAPK activation by the MAPK kinase inhibitor PD-98059 inhibited the IGF-I-stimulated DNA synthesis. Similarly, use of the PI3 kinase inhibitor LY-294002 also inhibited IGF-I-stimulated DNA synthesis. When both the MAPK and PI3 kinase pathways were inhibited using a combination of these compounds, the IGF-I-stimulated DNA synthesis was completely negated. These results indicate that both IGF-I and -II are potent mitogens for zebrafish embryonic cells and that activation of both the MAPK and PI3 kinase-signaling pathways is required for the mitogenic action of IGFs in zebrafish embryonic cells.
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PMID:IGFs stimulate zebrafish cell proliferation by activating MAP kinase and PI3-kinase-signaling pathways. 1124 49

The insulin-like growth factor I receptor (IGF-IR) activated by its ligands insulin-like growth factor (IGF)-I or IGF-II mediates suppression of apoptosis and contributes to tumorigenesis and cell growth. Here we investigated the activation of the stress-activated protein kinases including Jun N-terminal Kinases and p38 MAPK by IGF-I in interleukin-3-dependent FL5.12 lymphocytic cells that overexpress the IGF-IR (FL5.12/WT). We have shown previously that IGF-I protects these cells from apoptosis induced by interleukin-3 withdrawal but does not promote proliferation. IGF-I induced a rapid and transient activation of JNK that peaked at 40 min that was paralleled by a transient and robust phosphorylation of c-Jun. p38 was constitutively phosphorylated in FL5.12/WT cells. Activation of the JNK pathway by IGF-I occurred in the presence of phosphatidylinositol 3-kinase inhibitors and could be enhanced by anisomycin. Analysis of a series of FL5.12 cells expressing mutated IGF-IRs and analysis of 32D/IGF-IR cells showed that neither the C terminus of the receptor nor IRS-1 and IRS-2 were required for JNK activation, although tyrosine 950 was essential for full activation. The JNK inhibitor dicumarol suppressed IGF-I-mediated activation of JNK and phosphorylation of c-Jun but did not affect p38 and IkappaB phosphorylation or activation of AKT. IGF-I-mediated protection from apoptosis in FL5.12/WT cells was completely suppressed by dicumarol and partially suppressed by a p38 inhibitor. In the breast carcinoma cell line MCF-7, treatment with dicumarol also induced apoptosis. These data indicate that transient activation of JNK by IGF-I is mediated by signals that are distinct from those leading to phosphatidylinositol 3-kinase and AKT activation. The data further suggest that the SAPK pathways contribute to suppression of apoptosis by the IGF-IR.
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PMID:Transient activation of Jun N-terminal kinases and protection from apoptosis by the insulin-like growth factor I receptor can be suppressed by dicumarol. 1127 92


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