Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the mouse beta-PDGF receptor by gene transfer confers PDGF-dependent and reversible neuronal differentiation of PC12 pheochromocytoma cells similar to that observed in response to NGF and basic FGF. A common property of the PDGF, NGF, and basic FGF-induced differentiation response is the requirement for constant exposure of cells to the growth factor. To test the hypothesis that a persistent level of growth factor receptor signaling is required for the maintenance of the neuronal phenotype, we examined the regulation of the serine/threonine-specific MAP kinases after either short- (10 min) or long-term (24 h) stimulation with growth factors. Mono Q FPLC resolved two peaks of growth factor-stimulated MAP kinase activity that coeluted with tyrosine phosphorylated 41- and 43-kDa polypeptides. MAP kinase activity was markedly stimulated (approximately 30-fold) within 5 min of exposure to several growth factors (PDGF, NGF, basic FGF, EGF, and IGF-I), but was persistently maintained at 10-fold above basal activity after 24 h only by the growth factors that also induce PC12 cell differentiation (PDGF, NGF, and basic FGF). Thus the beta-PDGF receptor is in a subset of tyrosine kinase-encoded growth factor receptors that are capable of maintaining continuous signals required for differentiation of PC12 cells. These signals include the constitutive activation of cytoplasmic serine/threonine protein kinases.
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PMID:The beta-PDGF receptor induces neuronal differentiation of PC12 cells. 131 43

We have shown that FGF (basic or acidic) is mitogenic for quiescent hamster lung fibroblasts (CCL39 line). It is active alone but is much more efficient in synergistic combinations with G-protein-activating agents. When used alone, FGF appears to exert its mitogenic effects without involving any of the major G-protein-mediated signaling pathways. It causes no significant hydrolysis of phosphoinositides, it does not alter the activity of adenylate cyclase, and its mitogenicity is insensitive to pertussis toxin. It therefore seems likely that all pleiotropic actions of FGF are primarily mediated by the intrinsic protein tyrosine kinase of its receptors. However, FGF, acting through its receptor tyrosine kinase, and thrombin, acting through G-protein-coupled receptors, induce a common set of early responses detected within seconds or minutes at the level of membranes, cytoplasm, and nuclei. Typical examples of early responses are activation of Na/H antiporter and Na/K/Cl cotransporter, phosphorylation of ribosomal protein S6, and increased transcription of early-immediate genes (c-fos, c-jun, and c-myc). Not only various classes of growth factors acting via distinct transducing mechanisms activate common targets, but also their synergistic effects on reinitiation of DNA synthesis is reflected on the early responses. How does the coordination of these signaling events take place? A partial answer to this question is illustrated in Figure 6 in which "switch kinases" play the role of integrators of multiple extracellular signals. Raf and, perhaps more convincingly, MAP kinases that are activated by dual phosphorylation on tyrosine and threonine residues are potential good candidates for this integration. This hypothetical scheme could therefore explain, in part, the coordination and the synergy commonly observed in the mitogenic response. The synergy could be generated at the level of MAP kinases simply by dual activating phosphorylations. With the recent cloning of MAP kinases, these questions will be more easily addressed. Another important gap that will have to be filled in future studies is the identification of all the members of the kinase cascade. When used in synergistic combinations with G-protein-activating agents, FGF does exert in contrast some effects on the G-protein-mediated pathways. It potentiates the G-protein-mediated activations of both PIP2-PLC and adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mitogenic effects of fibroblast growth factors in cultured fibroblasts. Interaction with the G-protein-mediated signaling pathways. 166 81

We have successfully established normal neonatal and adult human melanocyte cultures in a growth medium containing the physiologic mitogens basic fibroblast growth factor (bFGF; 0.6 ng/ml), endothelin-1 (endo-1; 10 nM), and alpha-melanocyte stimulating hormone (alpha-MSH; 10 nM). The latter two factors replaced the commonly used mitogens 12-O-tetradecanoylphorbol 13-acetate (TPA) and bovine pituitary extract (BPE), respectively. Basic FGF alone maintained the viability but did not induce the proliferation of melanocytes. The addition of endo-1 to the bFGF-containing medium resulted in reduction of tyrosinase activity without enhancement of proliferation. However, the addition of alpha-MSH to the bFGF-containing medium potentiated melanocyte proliferation and tyrosinase activity. The concomitant addition of endo-1, alpha-MSH, and bFGF significantly increased the entry of melanocytes into S phase and potentiated their proliferation. Melanocytes maintained under these conditions had the same tyrosinase activity as those maintained in a medium containing alpha-MSH and bFGF. The signal transduction pathway induced by either endo-1 or bFGF, but not alpha-MSH, includes the activation of the mitogen-activated (MAP) kinase pathway. The addition of both endo-1 and bFGF had more than an additive effect on the MAP kinase extracellular signal-regulated kinase 2 (ERK2). This effect was further increased by the addition of alpha-MSH to these two growth factors. In summary, we have devised a growth medium for human melanocytes based on the use of physiologic mitogens that substituted for routinely used artificial and undefined growth factors. The resulting cultures should be desirable for clinical uses and permissive for the expression of in vivo relevant responses to regulatory factors.
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PMID:Long-term proliferation of human melanocytes is supported by the physiologic mitogens alpha-melanotropin, endothelin-1, and basic fibroblast growth factor. 769 46

Cell proliferation is regulated by an appropriate combination of intracellular signals involving activation of kinases and the generation of phospholipid metabolites. We report here that growth factors induce a biphasic generation of phosphorylcholine (PCho) in quiescent NIH 3T3 cells, resulting in an early and transient increase at 100 s and a larger and sustained increase after 3 h of stimulation. Generation of PCho at both early and late times of growth factors stimulation results from the consecutive activation of phospholipase D (PLD) and choline kinase (ChoK). Production of PCho by specific growth factors seems an essential requirement for the early signals associated to activation of Raf-1 and MAP kinases, since blockage of choline kinase completely inhibited activation of Raf-1 and MAP kinases by PDGF or FGF. Both the transient early increase and the late sustained increase in PCho are required for the induction of DNA-synthesis, besides completion of the activation of the serine/threonine kinases cascade. Thus, our results strongly suggest that generation of PCho by the PLD/choline kinase pathway is one of the critical steps in regulating cell growth in NIH 3T3 stimulated by growth factors.
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PMID:Generation of phosphorylcholine as an essential event in the activation of Raf-1 and MAP-kinases in growth factors-induced mitogenic stimulation. 772 53

We have examined the role of MAP kinase during mesoderm induction and axial patterning in Xenopus embryos. MAP Kinase Phosphatase (MKP-1) was used to inactivate endogenous MAP kinase and was found to prevent the induction of early and late mesodermal markers by both FGF and activin. In whole embryos, MKP-1 was found to disrupt posterior axial patterning, generating a phenotype similar to that obtained with a dominant inhibitory FGF receptor. Overexpression of either constitutively active MAP kinase or constitutively active MAP kinase (MEK) was sufficient to induce Xbra expression, while only constitutively active MEK was able to significantly induce expression of muscle actin. When MAP kinase phosphorylation was used as a sensitive marker of FGF receptor activity in vivo, this activity was found to persist at a low and relatively uniform level throughout blastula stage embryos. The finding that a low level of MAP kinase phosphorylation exists in unstimulated animal caps and is absent in caps overexpressing a dominant inhibitory FGF receptor provides a basis for our previous observation that overexpression of this receptor inhibits activin induction. These results indicate that FGF-dependent MAP kinase activity plays a critical role in establishing the responsiveness of embryonic tissues to mesoderm inducers.
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PMID:Role of MAP kinase in mesoderm induction and axial patterning during Xenopus development. 778 77

The peptide hormone angiotensin II (AngII) has clearly defined physiologic roles as a regulator of vasomotor tone and fluid homeostasis. In addition AngII has trophic or mitogenic effects on a variety of target tissues, including vascular smooth muscle and adrenal cells. More recent data indicate that AngII exhibits many characteristics of the 'classical' peptide growth factors such as EGF/TGF alpha, PDGF and IGF-1. These include the capacity for local generation ('autocrine or paracrine' action) and the ability to stimulate tyrosine phosphorylation, to activate MAP kinases and to increase expression of nuclear proto-oncogenes. The type 1 AngII receptor, which is responsible for all known physiologic actions of AngII, has been cloned. Activation of this receptor leads to elevated phosphoinositide hydrolysis, mobilization of intracellular Ca2+ and diacylglycerol, and activation of Ca2+/calmodulin and Ca2+/phospholipid-dependent Ser/Thr kinases, as well as Ca2+ regulated tyrosine kinases. The existence of other AngII receptor subtypes has been postulated, but the function(s) of these sites remains unclear. In vascular smooth muscle, AngII can promote cellular hypertrophy and/or hyperplasia, depending in part on the patterns of induction of secondary factors that are known to stimulate (PDGF, IGF-1, basic FGF) or inhibit (TGF-beta) mitosis. Together, these findings have suggested that AngII plays important roles in both the normal development and pathophysiology of vascular, cardiac, renal and central nervous system tissues.
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PMID:Regulation of cell proliferation and growth by angiotensin II. 791 23

Basic fibroblast growth factor (bFGF) is a potent mitogen for bone. In this study, we utilized the clonal rat osteoblastic cell line, Py1a, to examine signal transduction by bFGF and to determine the role of mitogen activated protein kinases (MAPK) and induction of c-fos mRNA in the mitogenic response to bFGF. Stimulation of [3H]thymidine incorporation (TDR) into DNA by bFGF was determined in the presence of phorbol myristate acetate of (PMA) to down-regulate the protein kinase C (PKC) pathway, genistein, an inhibitor of tyrosine kinase and H-7, a PKC inhibitor, bFGF 10(-8) M and PMA 10(-7) M increased TDR by 242 and 245%, respectively. Treatment with bFGF or PMA for 5 or 30 minutes increased tyrosine phosphorylation of multiple proteins, and immunoblotting with MAPK-specific antibody revealed that two of these bands were the 42 and 44 kD isoforms of MAPK. PMA and bFGF induced c-fos mRNA expression at 30 minutes. Genistein at 10 micrograms/ml blocked the mitogenic effect of bFGF and partially inhibited the mitogenic effect of PMA. Genistein at 100 micrograms/ml also blocked both bFGF- and PMA-induced increases in c-fos mRNA. A 24 h pretreatment with PMA at 10(-7) M inhibited the mitogenic response, tyrosine phosphorylation of MAPK, and induction of c-fos mRNA subsequent to the addition of PMA, but not bFGF. H-7 at 50 microM blocked bFGF-induced mitogenesis and c-fos induction, but did not inhibit bFGF-induced tyrosine phosphorylation of MAPK. In this study, we show that the signaling pathway of bFGF and PMA are similar in that they both induce tyrosine phosphorylation of MAP kinases and activate c-fos. However, the signaling pathways ultimately diverge in that once the PKC pathway is down-regulated by PMA pretreatment or blocked by the PKC inhibitor H-7, tyrosine phosphorylation of MAP kinase, c-fos induction, and the mitogenic effect of PMA is blocked. In contrast, down-regulation of the PKC pathway inhibits c-fos and the mitogenic response to bFGF, but not bFGF's effects on tyrosine phosphorylation of MAP kinase.
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PMID:Signal transduction by basic fibroblast growth factor in rat osteoblastic Py1a cells. 886

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.
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PMID:Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. 897 28

Wound reepithelialization and keratinocyte migration require strictly ordered gene expression, which is assumed to be initiated by locally released mitogens and exposure of the cells to different matrix components. The mechanisms triggering gene expression specifically during reepithelialization are poorly understood. The far upstream AP-1-driven, FGF-inducible response element (FiRE) of the syndecan-1 gene was activated during cutaneous wound healing in transgenic mice. FiRE was induced selectively in migrating but not in proliferating keratinocytes at the wound edge. The activation was initiated at the start of the cell migration, was persistent throughout the merging and stratification phases, and was terminated after completion of reepithelialization. Although FiRE has been found within the gene of syndecan-1, the proximal promoter of syndecan-1 was not required for activation of FiRE in the migrating keratinocytes. The wounding induced activation was inhibited by blocking cell surface growth factor receptors with suramin. However, the activation of FiRE in resting skin required simultaneous growth factor- and stress-induced signals, but could also be elicited by the phosphatase inhibitor, okadaic acid. The activation by both wounding and chemical stimuli was blocked by inhibiting extracellular regulated kinase and p38 MAP kinases, suggesting the involvement of at least two parallel signal transduction pathways in wounding induced gene activation. As FiRE shows specificity for migrating keratinocytes only, it can be a useful tool for future wound healing studies and for targeting genes to injured tissues.
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PMID:Wound reepithelialization activates a growth factor-responsive enhancer in migrating keratinocytes. 970 68

The SH2/SH3 adapters Nck, Grb2 and Crk promote the assembly of signaling complexes by binding to tyrosine phosphorylated proteins using their SH2 domains and to proline-rich sequences on effector molecules using their SH3 domains. FGF, which activates a receptor tyrosine kinase, induces mesoderm formation in Xenopus embryos through activation of the Ras/Raf/MAPK signaling pathway. We present evidence that dominant-negative mutants of Nck and Grb2, but not Crk1, can inhibit mesoderm-specific gene induction by eFGF in Xenopus animal cap explants. We also show that dominant-negative mutants of Grb2 and Nck can inhibit eFGF-induced Erk1 activation in Xenopus animal caps, and that targeting the first two SH3 domains of Nck to the membrane can activate Erk1 in the absence of eFGF. Furthermore, combinations of the dominant-negative Grb2 mutants with the inhibitory Nck mutant synergistically inhibited Erk1 activation by eFGF in Xenopus animal caps, suggesting that the dominant-negative Nck and Grb2 mutants inhibit Erk1 activation by binding to different proteins. By contrast only Grb2 mutants could inhibit eFGF-induced Erk1 activation in human 293 cells, demonstrating diversity in the specific mechanisms of signaling from FGF to MAP kinases in different cells.
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PMID:Dominant-negative mutants of the SH2/SH3 adapters Nck and Grb2 inhibit MAP kinase activation and mesoderm-specific gene induction by eFGF in Xenopus. 981 47


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