Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The structural characteristics of EMS1 (human cortactin) suggest that it may link signaling events to reorganization of the actin cytoskeleton. Interestingly, the EMS1 gene is commonly amplified and overexpressed in several human cancers, which may alter their invasive or metastatic properties. An 80 to 85-kDa mobility shift of EMS1 correlates with an alteration in subcellular distribution and is likely to represent an important regulatory event. In HEK 293 cells, epidermal growth factor treatment or cell detachment induced this shift, and this was blocked by the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059. Furthermore, expression of a constitutively active form of MEK induced the shift, indicating that MEK activation was both sufficient and necessary for this modification. The epidermal growth factor-induced shift correlated with increased phosphorylation on serine and threonine residues of the same tryptic phosphopeptides detected under basal conditions. Deletion of the helical-proline-rich region of the protein blocked the mobility shift and EMS1 phosphorylation. In vitro kinase assays demonstrated that the extracellular signal-regulated kinases represent candidate kinases for this region, although other MEK-regulated enzymes must also participate. These data identify MEK as an important intermediate involved in EMS1 phosphorylation and highlight the helical-proline-rich region as a key regulatory domain.
Cancer Res 1999 Oct 15
PMID:Signaling pathways and structural domains required for phosphorylation of EMS1/cortactin. 1053 23

Cancer progression to the invasive and metastatic stage represents the most formidable barrier to successful treatment. To develop rational therapies, we must determine the molecular bases of these transitions. Cell motility is one of the defining characteristics of invasive tumors, enabling tumors to migrate into adjacent tissues or transmigrate limiting basement membranes and extracellular matrices. Invasive tumor cells have been demonstrated to present dysregulated cell motility in response to extracellular signals from growth factors and cytokines. Recent findings suggest that this growth factor receptor-mediated motility is one of the most common aberrations in tumor cells leading to invasiveness and represents a cellular behavior distinct from-adhesion-related haptokinetic and haptotactic migration. This review focuses on the emerging understanding of the biochemical and biophysical foundations of growth factor-induced cell motility and tumor cell invasiveness, and the implications for development of targeted agents, with particular emphasis on signaling from the epidermal growth factor (EGF) and hepatocyte growth factor (HGF) receptors, as these have most often been associated with tumor invasion. The nascent models highlight the roles of various intracellular signaling pathways including phospholipase C-gamma (PLC gamma), phosphatidylinositol (PI)3'-kinase, mitogen-activated protein (MAP) kinase, and actin cytoskeleton-related events. Development of novel agents against tumor invasion will require not only a detailed appreciation of the biochemical regulatory elements of motility but also a paradigm shift in our approach to and assessment of cancer therapy.
Adv Cancer Res 2000
PMID:Tumor invasion: role of growth factor-induced cell motility. 1054 68

Epidermal growth factor receptor (EGFR) levels predict a poor outcome in human breast cancer and are most commonly associated with proliferative effects of epidermal growth factor (EGF), with little emphasis placed on motogenic responses to EGF. We found that MDA-MB-231 human breast cancer cells elicited a potent chemotactic response despite their complete lack of a proliferative response to EGF. Antagonists of EGFR ligation, the EGFR kinase, phosphatidylinositol 3'-kinase, and phospholipase C, but not the mitogen-activated protein kinases (extracellular signal-regulated protein kinase 1 and 2), blocked MDA-MB-231 chemotaxis. These findings suggest that EGF may influence human breast cancer progression via migratory pathways, the signaling for which appears to be dissociated, at least in part, from the proliferative pathways.
Cancer Res 1999 Nov 01
PMID:Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3'-kinase and phospholipase C-dependent mechanism. 1055 21

The growth factor-activated mitogenic pathways are often disregulated in tumour cells and, therefore, they can provide specific molecular targets for novel anti-tumour approaches. 8-Chloro-cAMP (8-Cl-cAMP), a synthetic cAMP analogue, is a novel anti-tumour agent that has recently undergone clinical evaluation. We investigated the effects of 8-Cl-cAMP on the epidermal growth factor (EGF)/EGF receptor (EGF-R) signalling in human epidermoid cancer KB cells, which are responsive to the mitogenic stimulus of EGF. We found that the growth-promoting activity of EGF was completely abolished when EGF treatment was performed in combination with 8-Cl-cAMP. The inhibition of the EGF-induced proliferation by 8-Cl-cAMP was paralleled by the blockade of the EGF-stimulated activation of mitogen-activated protein kinases (MAPK), ERK-1 and ERK-2. Conversely, we found an increase of EGF-R expression and EGF-R tyrosine phosphorylation when KB cells were growth inhibited by 8-Cl-cAMP. Moreover, the activity of Raf-1 and MEK-1 protein kinases, the activators upstream MAPK in the phosphorylation cascade induced by EGF, was not modified in 8-Cl-cAMP-treated cells. We concluded that the impairment of KB cell response to EGF, induced by 8-Cl-cAMP, resides in the specific inhibition of MAPK/ERKs activity while the function of the upstream elements in the EGF-R signalling is preserved.
Br J Cancer 1999 Dec
PMID:8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor. 1058 73

Perturbation of hepatocyte growth regulation is associated with a number of liver diseases such as fibrosis and cancer. These diseases are mediated by a network of growth factors and cytokines that regulate the induction of hepatocyte proliferation and apoptosis. In this study, we have investigated the role of signaling pathways activated by tumor necrosis factor alpha (TNF-alpha) and epidermal growth factor (EGF) in the regulation of apoptosis induced by transforming growth factor beta(1) (TGF-beta(1)), because this physiological factor is believed to regulate spontaneous apoptosis in the liver. We show that pretreatment with (10 ng/mL) EGF or (25 ng/mL) TNF-alpha can suppress TGF-beta(1)-induced apoptosis by 73% and 50%, respectively, in isolated rat hepatocytes. However, suppression of TGF-beta(1)-induced apoptosis by EGF and TNF-alpha occurs via different protein kinase signaling pathways. Using specific inhibitors, we show that suppression of apoptosis by EGF is dependent on activation of phosphoinositide 3-kinase (PI 3-kinase) and the extracellular signal regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathways, but not p38 MAP kinase. In contrast, suppression of TGF-beta(1)-induced apoptosis by TNF-alpha does not require PI 3-kinase and protein kinase B (PKB or Akt)-mediated pathways, but is dependent on ERK and p38 MAP kinase activity. These data contribute to our understanding of the intracellular survival signals that play a role in normal liver homeostasis and in diverse pathological conditions.
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PMID:The role of protein kinase B and mitogen-activated protein kinase in epidermal growth factor and tumor necrosis factor alpha-mediated rat hepatocyte survival and apoptosis. 1065 66

A possible link between oncogenes and tumor angiogenesis has been implicated by the finding that expression of various oncogenes, particularly mutant ras, can lead to a marked induction of a potent paracrine stimulator of angiogenesis, vascular endothelial growth factor (VEGF). We sought to determine how oncogenic ras induction of VEGF is mediated at the molecular level and whether the mechanisms involved differ fundamentally between transformed epithelial cells and fibroblasts. Our results suggest that in a subline (called RAS-3) of immortalized nontumorigenic rat intestinal epithelial cells (IEC-18) that acquired a tumorigenic phenotype upon transfection of mutant ras, up-regulation of VEGF occurs in the absence of an autocrine growth factor circuit. The expression of VEGF mRNA and protein by RAS-3 cells was strongly suppressed in the presence of LY294002, an inhibitor of phosphatidylinositol 3'-kinase, but remained largely unaffected in the same cells treated with an inhibitor (PD98059) of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MKK/MEK-1). This is consistent with the observation that overexpression of a constitutively activated mutant of MEK-1 (AN3/ S222D) in the parental IEC-18 cells did not result in up-regulation of VEGF production. The impact of mutant ras on VEGF expression was also significantly amplified at high cell density, conditions under which RAS-3 cells became less sensitive to LY294002-induced VEGF down-regulation. In marked contrast to cells of epithelial origin, ras-transformed murine fibroblasts (3T3RAS) up-regulated VEGF in a manner that was strongly inhibitable by MEK-1 blockade (ie. treatment with PD98059), whereas these cells were relatively unaffected by treatment with the phosphatidylinositol 3'-kinase inhibitor LY294002. In addition, VEGF was up-regulated by 2-3-fold in NIH3T3 cells overexpressing mutant MEK-1. Collectively, the data suggest that the stimulatory effect of mutant ras on VEGF expression is executed in a nonautocrine and cell type-dependent manner and that it can be significantly exacerbated by physiological/ environmental influences such as high cell density.
Cancer Res 2000 Jan 15
PMID:Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. 1066 5

The 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. We have recently shown that 3beta-HSD type 1 gene expression is specifically induced by interleukin (IL)-4 and IL-13 in breast human cancer cell lines and in normal human mammary epithelial cells in primary culture. There is evidence that IL-4 stimulates bifurcating signaling pathways in which the signal transducer and activator of transcription-6 (Stat6)-signal pathway is involved in differentiation and gene regulation, whereas insulin receptor substrate (IRS) proteins mediate the mitogenic action of IL-4. In fact, we have shown that Stat6 was activated by IL-4 in all cell lines studied where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. The present study was designed to investigate the potential contribution of IRS proteins and their downstream targets to IL-4-induced 3beta-HSD type 1 gene expression. IL-4 rapidly induced IRS-1 and IRS-2 phosphorylation in ZR-75-1 human breast cancer cell lines. Moreover, insulin-like growth factor (IGF)-I and insulin, which are well known to cause IRS-1 and IRS-2 phosphorylation, increased the stimulatory effect of IL-4 on 3beta-HSD activity. IRS-1 and IRS-2 are adapter molecules that provide docking sites for different SH2-domain-containing proteins such as the phosphatidylinositol (PI) 3-kinase. In this light, the inhibition of IL-4-induced 3beta-HSD expression by wortmannin and LY294002, two potent PI 3-kinase inhibitors, indicates the probable involvement of the PI 3-kinase signaling molecules in this response to IL-4. Furthermore, it has been suggested that the IRS proteins are part of the signaling complexes that lead to activation of the mitogen-activated protein (MAP) kinase by insulin; thus we investigated the potential role of the MAP kinase (MAPK) cascade in the IL-4 action. In ZR-75-1 cells, both the activation of MAPK by IL-4 and the IL-4-induced 3beta-HSD activity were completely blocked by PD98059, an inhibitor of MAPK activation. Wortmannin also blocked MAPK activation by IL-4, IGF-I, and insulin, suggesting that the MAPK cascade acts as a downstream effector of PI 3-kinases. To further understand the cross-talk between signaling pathways involved in IL-4 action, we investigated the possible involvement of protein kinase C (PKC). The potential role of PKC was suggested by the observation that the well known PKC activator phorbol-12-myristate-13-acetate (PMA) potentiated the IL-4-induced 3beta-HSD activity. Taken together, these findings suggest the existence of a novel mechanism of gene regulation by IL-4. This mechanism would involved the phosphorylation of IRS-1 and IRS-2, which transduce the IL-4 signal through a PI 3-kinase- and MAPK-dependent signaling pathway. The inability of IGF-I, insulin, and PMA to stimulate 3beta-HSD expression by themselves in the absence of IL-4 makes obvious the absolute requirement of an IL-4-specific signaling molecule. Our findings thus suggest that the multiple pathways downstream of IRS-1 and IRS-2 must act in cooperation with the IL-4-specific transcription factor Stat6 to mediate the induction of 31beta-HSD type 1 gene expression in ZR-75-1 human breast cancer cells.
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PMID:Multiple signaling pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene expression in human breast cancer cells. 1067 96

Human placental alkaline phosphatase (PALP) is synthesized in the placenta during pregnancy and is also expressed in many cancer patients; however, its physiological role is unknown. Here we show that in human fetus fibroblasts as well as normal and H-ras-transformed mouse embryo fibroblasts PALP stimulates DNA synthesis and cell proliferation in synergism with insulin, zinc and calcium. The mitogenic effects of PALP are associated with the activation of c-Raf-1, p42/p44 mitogen-activated protein kinases, p70 S6 kinase, Akt/PKB kinase and phosphatidylinositol 3'-kinase. The results suggest that in vivo PALP may promote fetus development as well as the growth of cancer cells which express oncogenic Ras.
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PMID:Growth factor-like effects of placental alkaline phosphatase in human fetus and mouse embryo fibroblasts. 1071 64

Cellular growth and differentiation are controlled by multiple extracellular signals, many of which activate extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinases. Components of the MAP kinase pathways also cause oncogenic transformation in their constitutively active forms. Moreover, expression of activated ras can confer metastatic potential upon some cells. Activation of MAP kinases requires phosphorylation of both Thr and Tyr in the catalytic domain by a family of dual-specificity kinases, called MEKs (MAP kinase/ERK kinase). MEK1 is activated by phosphorylation at Ser218 and Ser222 by Raf. Mutation of these two sites to acidic residues, specifically [Asp218], [Asp218, Asp222], and [Glu218, Glu222], results in constitutively active MEK1. Using these mutant variants of MEK1, we showed previously that transfection of NIH/3T3 or Swiss 3T3 cells causes morphological transformation and increases growth on soft agar, independent of ERK activity. The transformed cell lines show increased expression of matrix metalloproteinases 2 and 9 and cathepsin L, proteinases that have been implicated in the metastatic process. We tested NIH3T3 cells transfected with the [Asp218] or [Asp218, Asp222] for metastatic potential after i.v. injection into athymic mice. Parental 3T3 cells formed no tumors grossly or histologically. However, all MEK1 mutant transformants formed macroscopic metastases. Thus, like activated Ras, MEK1 can confer both tumorigenic and metastatic potential upon NIH3T3 cells. These results refine the mechanism through which ras could confer tumorigenic and metastatic potential (ie., the critical determinants of tumorigenic and metastatic potential are downstream of MEK1).
Cancer Res 2000 Mar 15
PMID:Transfection of constitutively active mitogen-activated protein/extracellular signal-regulated kinase kinase confers tumorigenic and metastatic potentials to NIH3T3 cells. 1074 22

Endothelin (ET)-1, an endothelium-derived vasoconstrictor and mitogen, acts as an antiapoptotic factor against serum deprivation-induced apoptosis of endothelial cells and fibroblasts but enhances apoptosis of some cancer cells. In the present study, we examined whether nitric oxide (NO) and ET-1 modulate apoptosis of rat vascular smooth muscle cells (VSMCs) via the mitogen-activated protein (MAP) kinase pathway. Both serum deprivation and NO donors (FK409 and SNAP) caused apoptosis of VSMCs, as demonstrated by TdT-mediated dUTP-biotin nick end-labeling, appearance of fragmented DNA, and induction of caspase-3 activity. ET-1 dose-dependently antagonized apoptosis induced by serum deprivation and NO donors. A selective ET(A) receptor antagonist (BQ123) and a nonselective ET(A/B) receptor antagonist (TAK044), but not a selective ET(B) receptor antagonist (BQ788), inhibited the antiapoptotic effect of ET-1, indicating that the antiapoptotic effect of ET-1 is mediated via the ET(A) receptor. ET-1 activated MAP kinase, whose effect was inhibited by FK409. Transfection with an unphosphorylated wild-type MAP kinase kinase-1 (MAPKK-1) or its constitutively activated mutant protected VSMCs against apoptosis induced by serum deprivation and NO donors. Inhibition of MAP kinase activity with PD98059, a specific inhibitor of MAPKK-1, or by transfection of a dominant-negative MAPKK-1 mutant antagonized the antiapoptotic effect of ET-1, suggesting the involvement of MAP kinase in the antiapoptotic effect. The potent inhibitory effect of ET-1 on apoptosis of VSMCs induced by serum deprivation and NO suggests that the counterbalance between the 2 endothelium-derived factors contributes to the process of vascular remodeling by determining VSMC survival and death, respectively, via a common MAP kinase pathway.
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PMID:Endothelin-1 inhibits apoptosis of vascular smooth muscle cells induced by nitric oxide and serum deprivation via MAP kinase pathway. 1076 63


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