Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diverse extracellular stimuli activate the ERK1/2 MAPK cascade by transactivating epidermal growth factor (EGF) receptors. Here, we have examined the role of EGF receptors in IGF-I-stimulated ERK1/2 activation in several cultured cell lines. In human embryonic kidney 293 cells, IGF-I triggered proteolysis of heparin binding (HB)-EGF, increased tyrosine autophosphorylation of EGF receptors, stimulated EGF receptor inhibitor (AG1478)-sensitive ERK1/2 phosphorylation, and promoted EGF receptor endocytosis. In a mixed culture system that employed IGF-I receptor null murine embryo fibroblasts (MEFs) (R(-) cells) to detect paracrine signals produced by MEFs expressing the human IGF-I receptor (R(+) cells), stimulation of R(+) cells provoked rapid activation of green fluorescent protein-tagged ERK2 in cocultured R(-) cells. The R(-) cell response was abolished by either the broad-spectrum matrix metalloprotease inhibitor batimastat or by AG1478, indicating that it resulted from the proteolytic generation of an EGF receptor ligand from adjacent R(+) cells. These data suggest that the paracrine production of EGF receptor ligands leading to EGF receptor transactivation is a general property of IGF-I receptor signaling. In contrast, the contribution of transactivated EGF receptors to IGF-I-stimulated downstream events, such as ERK1/2 activation, varies in a cell type-dependent manner.
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PMID:Ectodomain shedding-dependent transactivation of epidermal growth factor receptors in response to insulin-like growth factor type I. 1527 55

Integrins are heterodimeric transmembrane proteins that mediate cell attachment to extracellular matrix, migration, division, and inhibition of apoptosis. Because growth factors are also important for these processes, there has been interest in cooperative signaling between growth factor receptors and integrins. IGF-I is an important growth factor for vascular cells. One integrin, alphaVbeta3, that is expressed in smooth muscle cells modulates IGF-I actions. Ligand occupancy of alphaVbeta3 is required for IGF-I to stimulate cell migration and division. Src homology 2 containing tyrosine phosphatase (SHP-2) is a tyrosine phosphatase whose recruitment to signaling molecules is stimulated by growth factors including IGF-I. If alphaVbeta3 ligand occupancy is inhibited, there is no recruitment of SHP-2 to alphaVbeta3 and its transfer to downstream signaling molecules is blocked. Ligand occupancy of alphaVbeta3 stimulates tyrosine phosphorylation of the beta3-subunit, resulting in recruitment of SHP-2. This transfer is mediated by an insulin receptor substrate-1-related protein termed DOK-1. Subsequently, SHP-2 is transferred to another transmembrane protein, SHPS-1. This transfer requires IGF-I receptor-mediated tyrosine phosphorylation of SHPS-1, which contains two YXXL motifs that mediate SHP-2 binding. The transfer of SHP-2 to SHPS-1 is also required for recruitment of Shc to SHPS-1. Ligand occupancy of alphaVbeta3 results in sustained Shc phosphorylation and enhanced Shc recruitment. Shc activation results in induction of MAPK. Inhibition of the Shc/SHPS-1 complex formation results in failure to achieve sustained MAPK activation and an attenuated mitogenic response. Thus, within the vessel wall, a mechanism exists whereby ligand occupancy of the alphaVbeta3 integrin is required for assembly of a multicomponent membrane signaling complex that is necessary for cells to respond optimally to IGF-I.
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PMID:Interaction between insulin-like growth factor-I receptor and alphaVbeta3 integrin linked signaling pathways: cellular responses to changes in multiple signaling inputs. 1552 74

The nuclear receptor coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I-stimulated anchorage-independent growth by reducing IGF-I-dependent anti-anoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-I-stimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen receptor signaling.
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PMID:The nuclear receptor coactivator AIB1 mediates insulin-like growth factor I-induced phenotypic changes in human breast cancer cells. 1554 98

Autocrine activation of the IGF-I system in mesangial cells (MC) promotes glomerular scarring in a model of type 1 diabetes. Although estrogens protect against progressive nondiabetic glomerulosclerosis (GS), women with diabetes seem to loose the estrogen-mediated protection against cardiovascular disease. However, little is known about the local IGF-I system and its interactions with estrogens in the pathogenesis of type 2 diabetic GS. Therefore, we examined db/db B6 (db/db) mice, a model of type 2 diabetes and diabetic GS. The IGF-I system was activated in the glomeruli and MC of female diabetic db/db mice, but not in nondiabetic db/+ littermates. We found increased IGF-I receptor (IGFR) expression and activation, including activation of MAPK. Surprisingly, estrogens, via an estrogen receptor (ER)-independent mechanism(s), increased IGFR expression, IGFR and insulin receptor substrate phosphorylation, and extracellular signal-regulated kinase activation in db/db MC. In contrast, ER expression was decreased in MC and glomeruli of db/db mice. Treatment with a neutralizing antibody to IGF-I or the MAPK inhibitor PD98059 increased ER expression and transcriptional activity. This suggests that the local prosclerotic IGF-I system is activated in type 2 diabetes and diminishes ER-mediated protection against GS. Although estrogens may stimulate protective ER signaling, they also activate the IGF-I system via ER-independent mechanisms in db/db MC. The later estrogen effects appear to outweigh the antisclerotic effects of ER activation. This may in part account for loss of estrogen protection against the progression of diabetic GS in women with type 2 diabetes.
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PMID:Autocrine activation of the local insulin-like growth factor I system is up-regulated by estrogen receptor (ER)-independent estrogen actions and accounts for decreased ER expression in type 2 diabetic mesangial cells. 1555 May 5

The IGFs promote the growth and development of the feto-placental unit during gestation, and impairment of their placental actions may result in altered intrauterine growth of the fetus. In this study, proteins involved in IGF signaling were investigated in human placentas from pregnancies complicated by intrauterine growth restriction (IUGR) compared with those from normal pregnancies. IUGR placentas exhibited 33% reduction in the protein content of IGF-I receptors, but no changes in insulin receptor protein levels. In addition, insulin receptor substrate-2 (IRS-2) protein levels were reduced in IUGR placentas, with no changes in IRS-1 or Shc protein content, and this was associated with a parallel decrease in IRS-2-associated phosphatidyl inositol 3-kinase. Akt protein expression was also reduced in IUGR, whereas phosphorylation of Akt and its substrate glycogen synthase kinase-3 was unchanged. Finally, in IUGR placentas there was impaired activation of multiple members of the MAPK family, because phosphorylation of p38 and c-Jun N-terminal kinase was reduced 70%. In conclusion, human placentas from pregnancies complicated by IUGR are characterized by decreased IGF-I receptor content, selective impairment of the IRS-2/ phosphatidyl inositol 3-kinase pathway, and reduced p38 and c-Jun N-terminal kinase activation. The observed abnormalities in IGF-I signaling may contribute to altered fetal growth and development in human IUGR.
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PMID:Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling. 1556 21

Resistin (Rstn) is known as an adipocyte-specific secretory factor that can cause insulin resistance and decrease adipocyte differentiation. Conversely, based on various studies, insulin-like growth factors (IGFs) can improve insulin resistance and stimulate adipocyte adipogenesis. Whether IGFs exert their effects through the control of Rstn's production or modulation of Rstn's action is unknown. This study was designed to examine the influence and the signaling of IGF-I on Rstn gene expression and protein secretion by 3T3-L1 adipocytes. We found that IGF-I suppressed Rstn mRNA expression and protein release in dose- and time-dependent manners. The IC50 of IGF-I was approximately 1 nM for a range of 6-10 h of treatment. Treatment with cycloheximide, but not with actinomycin D, prevented IGF-I-suppressed Rstn mRNA expression, suggesting that IGF-I destabilizes Rstn mRNA and that IGF-I's effect requires new protein, but not mRNA, synthesis. Pretreatment with IGF-I receptor (IGF-IR) antibody blocked IGF-I-altered IGF-IR activity and Rstn mRNA levels. Neither PD-98059, SB-203580, nor LY-294002 changed the IGF-I-decreased levels of Rstn mRNA, but they inhibited IGF-I-stimulated activities of MEK1, p38 MAPK, and phosphoinositide 3-kinase, respectively. However, SB-203580 antagonized the IGF-I-decreased Rstn protein release. These data demonstrate that IGF-I downregulates Rstn gene expression via IGF-IR-dependent and MEK1-, p38 MAPK-, and phosphoinositide 3-kinase-independent pathways and likely modifies the distribution of Rstn protein between the intracellular and extracellular compartments via a p38 MAPK-dependent pathway. Decreases in Rstn production and secretion induced by IGF-I may be related to the mechanism by which IGF-I modulates body weight and diabetes in animals.
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PMID:IGF-I downregulates resistin gene expression and protein secretion. 1558 89

Insulin-like growth factor binding protein-5 (IGFBP-5) and thrombospondin-1 (TS-1) are both present in extracellular matrix (ECM). Both proteins have been shown to bind to one another with high affinity. The purpose of these studies was to determine how the interaction between IGFBP-5 and TS-1 modulates IGF-I actions in porcine aortic smooth muscle cells (pSMC) in culture. The addition of increasing concentrations of TS-1 to pSMC cultures enhanced the protein synthesis and cell migration responses to IGF-I; whereas the addition of IGFBP-5 alone resulted in minimal changes. In contrast, the addition of IGFBP-5 to cultures that were also exposed to IGF-I and TS-1 resulted in inhibition of protein synthesis. When the cell migration response was assessed, the response to IGF-I plus TS-1 was also significantly inhibited by the addition of IGFBP-5, whereas 1.0 microg/ml of IGFBP-5 alone had no effect on the response to IGF-I. To determine the molecular mechanism by which this inhibition occurred, a mutant form of IGFBP-5 that does not bind to IGF-I was tested. This mutant was equipotent compared to native IGFBP-5 in its ability to inhibit both protein synthesis and cell migration responses to IGF-I plus TS-1 thus excluding the possibility that IGFBP-5 was inhibiting the response to TS-1 and IGF-I by inhibiting IGF-I binding to the IGF-I receptor. To determine if an interaction between TS-1 and IGFBP-5 was the primary determinant of the inhibitory effect of IGFBP-5, an IGFBP-5 mutant that bound poorly to TS-1 was utilized. The addition of 1.0 microg/ml of this mutant did not inhibit the protein synthesis or cell migration responses to IGF-I plus TS-1. To determine the mechanism by which IGFBP-5 binding to TS-1 inhibited cellular responses to TS-1 plus IGF-I, TS-1 binding to integrin associated protein (IAP) was assessed. The addition of IGFBP-5 (1.0 microg/ml) inhibited TS-1-IAP association. In contrast, a mutant form of IGFBP-5 that bound poorly to TS-1 had a minimal effect on TS-1 binding to IAP. Further analysis showed that IGFBP-5 addition altered the ability of TS-1 to modulate the SHPS-1/IAP interaction. When the IGFBP-5 mutant that did not bind to IGF-I was incubated with TS-1 and IGF-I, it inhibited the capacity of TS-1 to enhance the IGF-I receptor phosphorylation and MAP kinase activation in response to IGF-I. In contrast, the IGFBP-5 mutant that did not bind to TS-1 had no effect on IGF-I stimulated IGF-I receptor phosphorylation or MAP kinase activation. These results indicate that IGFBP-5 inhibits the binding of TS-1 to IAP, and this results in an alteration of the ability of TS-1 to modulate the disruption of the IAP/SHPS-1 interaction which leads to attenuation of the ability of TS-1 to enhance cellular responsiveness to IGF-I.
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PMID:Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with thrombospondin-1 to induce negative regulatory effects on IGF-I actions. 1570 Feb 81

Much evidence has suggested that sex steroid hormone-induced growth of uterine cells is mediated by polypeptide growth factors synthesized in uterine tissues. The present study aimed to clarify the effect of insulin-like growth factor-I (IGF-I) on the proliferation of mouse endometrial stromal cells obtained from immature mice. IGF-I and IGF-I receptor (type I) mRNAs were detected in the endometrial stromal cells. IGF-I increased bromodeoxyuridine (BrdU) uptake in the endometrial stromal cells, indicating an increase in DNA replication. E2 increased IGF-I mRNA levels in the endometrial stromal cells. IGF-I receptor is a tyrosine kinase receptor, and treatment with genistein, a tyrosine kinase inhibitor, reduced IGF-I-induced BrdU-uptake in the endometrial stromal cells. IGF-I signaling pathways involve mitogen-activated protein (MAP) kinase and phosphatidylinositol-3 kinase (PI-3 kinase). Treatment with 10(-7) M of the MAP kinase inhibitor PD098059 and 10(-5) M of the PI-3 kinase inhibitor LY294002 decreased IGF-I-induced BrdU-uptake in the endometrial stromal cells. However, LY294002 (10(-5) M) also decreased the BrdU-uptake in the absence of IGF-I treatment. These results suggest that endometrial IGF-I is involved in the proliferation of endometrial stromal cells in a paracrine or autocrine manner, and that the MAP kinase pathway is involved in DNA replication of endometrial stromal cells.
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PMID:Insulin-like growth factor-I stimulated DNA replication in mouse endometrial stromal cells. 1572 79

IGF-I stimulates cell growth through interaction of the IGF receptor with multiprotein signaling complexes. However, the mechanisms of IGF-I receptor-mediated signaling are not completely understood. We have previously shown that IGF-I-stimulated 3T3-L1 cell proliferation is dependent on Src activation of the ERK-1/2 MAPK pathway. We hypothesized that IGF-I activation of the MAPK pathway is mediated through integrin activation of Src-containing signaling complexes. The disintegrin echistatin decreased IGF-I phosphorylation of Src and MAPK, and blocking antibodies to (alpha)v and beta3 integrin subunits inhibited IGF-I activation of MAPK, suggesting that (alpha)v(beta)3 integrins mediate IGF-I mitogenic signaling. IGF-I increased ligand binding to (alpha)v(beta)3 as detected by immunofluorescent staining of ligand-induced binding site antibody and stimulated phosphorylation of the beta3 subunit, consistent with inside-out activation of (alpha)v(beta)3 integrins. IGF-I increased tyrosine phosphorylation of the focal adhesion kinase (FAK) Pyk2 (calcium-dependent proline-rich tyrosine kinase-2) to a much greater extent than FAK, and increased association of Src with Pyk2 but not FAK. The intracellular calcium chelator BAPTA prevented IGF-I phosphorylation of Pyk2, Src, and MAPK, suggesting that IGF-I activation of Pyk2 is calcium dependent. Transient transfection with a dominant-negative Pyk2, which lacks the autophosphorylation and Src binding site, decreased IGF-I activation of MAPK, but no inhibition was seen with transfected wild-type Pyk2. These results indicate that IGF-I signaling to MAPK is dependent on inside-out activation of (alpha)v(beta)3 integrins and integrin-facilitated multiprotein complex formation involving Pyk2 activation and association with Src.
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PMID:(alpha)v(beta)3 integrins and Pyk2 mediate insulin-like growth factor I activation of Src and mitogen-activated protein kinase in 3T3-L1 cells. 1576 Oct 30

Sex steroids and growth factors interact at the intracellular level in a variety of tissues to control numerous physiological functions. Oestrogen is known to stimulate prolactin synthesis and secretion, but the effect of insulin-like growth factor (IGF)-I is less clear. We used GH3 cells, a somatolactotroph cell line, to study the interaction of 17beta-oestradiol (E(2)) and IGF-I on prolactin protein levels and the intracellular mechanisms involved. Cell cultures were treated with E(2) (10 nM) and/or IGF-I (10 ng/ml) for 8 h. The real-time reverse transcriptase-polymerase chain reaction, Western blot and enzyme-immunoassay were used to determine changes in prolactin mRNA and protein levels. At this time-point, there were no significant changes in cell number, prolactin mRNA expression, or the amount of secreted prolactin. However, E(2) increased intracellular prolactin concentrations. IGF-I alone had no effect, but blocked the stimulatory effect of E(2). MAPK (ERK1/2) activation, as determined by Western blot analysis, increased with both E(2) and IGF-I, but not with the combination of these factors. The MAPK inhibitor PD98059 blocked the ability of E(2) to increase intracellular prolactin concentrations. Similarly, the IGF-I receptor antagonist, JB1, blocked the effect of E(2) on prolactin synthesis and MAPK activation, as did the oestrogen receptor antagonist ICI182 780. These results suggest that, to stimulate prolactin synthesis, E(2) activates the MAPK cascade and that this requires the presence of both oestrogen and IGF-I receptors.
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PMID:Oestrogen requires the insulin-like growth factor-I receptor for stimulation of prolactin synthesis via mitogen-activated protein kinase. 1579 60


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