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)

Heregulin beta1 (HRG), a combinatorial ligand for human growth factor receptors 3 and 4, is a regulatory polypeptide that promotes the differentiation of mammary epithelial cells into secretory lobuloalveoli. Emerging evidence suggests that the processes of secretory pathways, such as biogenesis and trafficking of vesicles in neurons and adipose cells, are regulated by the Rab family of low-molecular-weight GTPases. In this study, we identified Rab3A as a gene product induced by HRG. Full-length Rab3A was cloned from a mammary gland cDNA library. We demonstrated that HRG stimulation of human breast cancer cells and normal breast epithelial cells induces the expression of Rab3A protein and mRNA in a cycloheximide-independent manner. HRG-mediated induction of Rab3A expression was blocked by an inhibitor of phosphatidylinositol 3-kinase but not by inhibitors of mitogen-activated protein kinases p38(MAPK) and p42/44(MAPK). Human breast epithelial cells also express other components of regulated vesicular traffic, such as rabphilin 3A, Doc2, and syntaxin. Rab3A was predominantly localized in the cytosol, and HRG stimulation of the epithelial cells also raised the level of membrane-bound Rab3A. HRG treatment induced a profound alteration in the cell morphology in which cells displayed neuron-like membrane extensions that contained Rab3A-coated, vesicle-like structures. In addition, HRG also promoted the secretion of cellular proteins from the mammary epithelial cells. The ability of HRG to modify exocytosis was verified by using a growth hormone transient-transfection system. Analysis of mouse mammary gland development revealed the expression of Rab3A in mammary epithelial cells. Furthermore, expression of the HRG transgene in Harderian tumors in mice also enhanced the expression of Rab3A. These observations provide new evidence of the existence of a Rab3A pathway in mammary epithelial cells and suggest that it may play a role in vesicle trafficking and secretion of proteins from epithelial cells in response to stimulation by the HRG expressed within the mammary mesenchyma.
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PMID:Evidence of Rab3A expression, regulation of vesicle trafficking, and cellular secretion in response to heregulin in mammary epithelial cells. 1107 7

Signals of interleukin 6 (IL-6) are transduced by binding of IL-6 to its cell surface receptor (IL-6R) and subsequent association of the resultant IL-6/IL-6R complex with gp130, the signal transducing receptor component utilized in common by all the IL-6 family of cytokines. A soluble form of IL-6R (sIL-6R), which lacks transmembrane and cytoplasmic regions, retains the ability to bind IL-6 and signal through gp130. We show here that a fusion protein of sIL-6R and IL-6 without a polypeptide linker, termed FP6, induces differentiation of astrocytes from fetal mouse neuroepithelial cells as potently as a representative IL-6 family cytokine, leukaemia inhibitory factor (LIF). FP6 has a potential to activate a transcription factor, signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases, ERK1 and ERK2, in these cells as does LIF. FP6 activates a promoter of the gene for an astrocytic marker, glial fibrillary acidic protein (GFAP), in neuroepithelial cells. This activation is virtually abolished by ectopic expression of a dominant-negative form of STAT3, or by introducing a point mutation into the STAT3 response element located in the GFAP promoter. These results suggest that FP6 induces astrocyte differentiation from neuroepithelial cells through STAT3 activation and that FP6 could be of use as a substitute for natural IL-6 family cytokines.
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PMID:Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3. 1124 5

Erk1 (p44) and erk2 (p42) mitogen-activated protein (MAP) kinases are activated in agonist-stimulated platelets, although their role(s) in the activation process is unknown. In the present study, erk1, erk2 and the phosphorylated forms of both enzymes became associated with the contractile cytoskeleton in thrombin-stimulated platelets. Enzyme incorporation was accompanied by an increase in MAP kinase activity in the cytoskeleton, which was inhibited by PD98059. Pretreatment of the platelets with the arginine-glycine-aspartic acid-serine (RGDS) polypeptide enhanced both the cytoskeletal association and the enzyme activity, but cytochalasin D had no significant effect. Platelets from a patient with Glanzmann's thrombasthenia lack the alpha(IIb)beta(3) integrin and form only a rudimentary cytoskeleton, however, this cytoskeleton is enriched with both erk1 and erk2. These data suggest either that MAP kinases play a role in cytoskeletal rearrangement or that the cytoskeleton act as a frame to align MAP kinases with substrates in a highly integrated signal transduction pathway.
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PMID:Incorporation of map kinases into the platelet cytoskeleton. 1143 43

The mitogen-activated protein (MAP) kinase ERK2 is an essential signal transduction molecule that mediates extracellular signaling by all polypeptide growth factors. Full activation of ERK2 requires phosphorylation at both a threonine residue (Thr(183)) conserved in most protein kinases as well as a tyrosine residue (Tyr(185)) unique to members of the mitogen-activated protein kinase family. We have characterized the kinetic role of phosphorylation at each site with respect to the overall activation mechanism, providing a complete picture of the reaction steps involved. Phosphorylation at Tyr(185) serves to configure the ATP binding site, while phosphorylation at both residues is required to stabilize binding of the protein substrate, myelin basic protein. Similar control mechanisms are employed to stabilize ATP and myelin basic protein in the phosphoryl group transfer reaction, accounting for the enormous increase in turnover rate. The mechanism of ERK2 activation is kinetically similar to that of the cell cycle control protein, cdk2/cyclinA. Phosphorylation of Tyr(185) in ERK2 and association of cyclinA with cdk2 both serve to stabilize ATP binding. Subsequent phosphorylation of both enzymes on threonine serves to stabilize binding of the phosphoacceptor substrate.
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PMID:The complete pathway for catalytic activation of the mitogen-activated protein kinase, ERK2. 1152 22

In neonatal cardiomyocytes, activation of the G(q)-coupled alpha(1)-adrenergic receptor (alpha(1)AR) induces hypertrophy by activating mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase (JNK). Here, we show that JNK activation is essential for alpha(1)AR-induced hypertrophy, in that alpha(1)AR-induced hypertrophic responses, such as reorganization of the actin cytoskeleton and increased protein synthesis, could be blocked by expressing the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of JNK. We also identified the classes and subunits of G proteins that mediate alpha(1)AR-induced JNK activation and hypertrophic responses by generating several recombinant adenoviruses that express polypeptides capable of inhibiting the function of specific G-protein subunits. alpha(1)AR-induced JNK activation was inhibited by the expression of carboxyl terminal regions of Galpha(q), Galpha(12), and Galpha(13). JNK activation was also inhibited by the Galpha(q/11)- or Galpha(12/13)-specific regulator of G-protein signaling (RGS) domains and by C3 toxin but was not affected by treatment with pertussis toxin or by expression of the carboxyl terminal region of G protein-coupled receptor kinase 2, a polypeptide that sequesters Gbetagamma. alpha(1)AR-induced hypertrophic responses were inhibited by Galpha(q/11)- and Galpha(12/13)-specific RGS domains, C3 toxin, and the carboxyl terminal region of G protein-coupled receptor kinase 2 but not by pertussis toxin. Activation of Rho was inhibited by carboxyl terminal regions of Galpha(12) and Galpha(13) but not by Galpha(q). Our findings suggest that alpha(1)AR-induced hypertrophic responses are mediated in part by a Galpha(12/13)-Rho-JNK pathway, in part by a G(q/11)-JNK pathway that is Rho independent, and in part by a Gbetagamma pathway that is JNK independent.
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PMID:Galpha(12/13) mediates alpha(1)-adrenergic receptor-induced cardiac hypertrophy. 1243 42

Protein kinase C (PKC) is involved in several cell events including proliferation, survival and differentiation. The aim of this work was to investigate the role of PKC activation on retinal cells proliferation. We demonstrated that PKC activation by phorbol 12-myristate 13-acetate (PMA), a tumor promoter phorbol ester, is able to decrease retinal cells proliferation. This effect was mediated by M1 receptors and dependent on intracellular Ca(2+) increase, tyrosine kinase activity, phosphatidylinositol 3-kinase activity, polypeptide secretion and activation of TrkB receptors. The effect of PMA was not via activation of mitogen-activated protein (MAP) kinase. Carbamylcholine and brain derived neurotrophic factor were both able to decrease retinal cells proliferation to the same level as PMA did. Our results suggest that PKC activation leads to a decrease in retinal cells proliferation through the release of acetylcholine and brain derived neurotrophic factor in the culture, and activation of M1 and TrkB receptors, respectively.
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PMID:PMA decreases the proliferation of retinal cells in vitro: the involvement of acetylcholine and BDNF. 1244 Nov 70

Tumor necrosis factor-alpha converting enzyme (TACE) is a prototype member of the adamalysin family of transmembrane metalloproteases that effects ectodomain cleavage and release of many transmembrane proteins, including transforming growth factor-alpha. Growth factors that act through tyrosine kinase receptors, as well as other stimuli, induce shedding through activation of the Erk mitogen-activated protein (MAP) kinase pathway without the need of new protein synthesis. How MAP kinase regulates shedding by TACE is not known. We now report that the cytoplasmic domain of TACE is phosphorylated in response to growth factor stimulation. We also identified a naturally expressed smaller polypeptide corresponding to most of the cytoplasmic domain of TACE. This protein, which we named SPRACT, is derived through alternative translation of the TACE-coding sequence and is, similarly to TACE, phosphorylated in response to growth factor and phorbol 12-myristate 13-acetate stimulation. Phosphoamino acid analysis revealed that growth factor-induced phosphorylation of TACE occurs only on serine and not on threonine or tyrosine. Tryptic mapping experiments coupled with site-directed mutagenesis identified Ser(819) as the major target of growth factor-induced phosphorylation, whereas Ser(791) undergoes dephosphorylation in response to growth factor stimulation. The phosphorylation of Ser(819), but not the dephosphorylation of Ser(791), depends on activation of the Erk MAP kinase pathway. Increased SPRACT expression or mutation of the TACE cytoplasmic domain to inactivate growth factor-induced phosphorylation did not detectably affect growth factor-induced shedding of transmembrane transforming growth factor-alpha by TACE. The roles of SPRACT and the cytoplasmic phosphorylation of TACE remain to be defined.
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PMID:Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-alpha converting enzyme and of an alternatively translated polypeptide. 1262 Oct 58

We have previously shown that Gq protein-coupled receptor (GqPCR) agonists stimulate epidermal growth factor receptor (EGFr) transactivation and activation of mitogen-activated protein kinases (MAPK) in colonic epithelial cells. This constitutes a mechanism by which Cl- secretory responses to GqPCR agonists are limited. In the present study we examined a possible role for the EGFr in regulating Cl- secretion stimulated by agonists that act through GsPCRs. All experiments were performed using monolayers of T84 colonic epithelial cells grown on permeable supports. Protein phosphorylation and protein-protein interactions were analyzed by immunoprecipitation and Western blotting. Cl- secretion was measured as changes in short-circuit current (DeltaIsc) across voltage-clamped T84 cells. The GsPCR agonist, vasoactive intestinal polypeptide (VIP; 100 nM), rapidly stimulated EGFr phosphorylation in T84 cells. This effect was mimicked by a cell-permeant analog of cAMP, Bt2cAMP/AM (3 microM), and was attenuated by the protein kinase A (PKA) inhibitor, H-89 (20 microM). The EGFr inhibitor, tyrphostin AG1478 (1 microM), inhibited both Bt2cAMP/AM-stimulated EGFr phosphorylation and Isc responses. VIP and Bt2cAMP/AM both stimulated ERK MAPK phosphorylation and recruitment of the p85 subunit of phosphatidylinositol 3-kinase (PI3K) to the EGFr in a tyrphostin AG1478-sensitive manner. The PI3K inhibitor, wortmannin (50 nM), but not the ERK inhibitor, PD 98059 (20 microM), attenuated Bt2cAMP/AM-stimulated secretory responses. We conclude that GsPCR agonists rapidly transactivate the EGFr in T84 cells by a signaling pathway involving cAMP and PKA. Through a mechanism that likely involves PI3K, transactivation of the EGFr is required for the full expression of cAMP-dependent Cl- secretory responses.
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PMID:Gs protein-coupled receptor agonists induce transactivation of the epidermal growth factor receptor in T84 cells: implications for epithelial secretory responses. 1466 Jun 4

Germinal center kinase (GCK), a member of the Ste20 family, selectively activates the Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases. Here, we show that endogenous GCK is activated by polyinosine-polycytidine [poly(IC)] and lipopolysaccharides (LPS), lipid A, interleukin-1 (IL-1), and engagement of CD40, all agonists that require TRAF6 for JNK activation. RNA interference experiments indicate that GCK is required for the maximal activation of JNK by LPS, lipid A, poly(IC), and, to a lesser extent, IL-1 and engagement of CD40. GCK is ubiquitinated in situ and stabilized by inhibitors of the proteasome, indicating that GCK is subject to proteasomal turnover. GCK is constitutively active, and the kinase activity of GCK is required for GCK ubiquitination. Agonist activation of GCK involves the TRAF6-dependent transient stabilization of the GCK polypeptide rather than an increase in intrinsic kinase activity. Our results identify a physiologic function and unexpected mode of regulation for GCK.
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PMID:Germinal center kinase is required for optimal Jun N-terminal kinase activation by Toll-like receptor agonists and is regulated by the ubiquitin proteasome system and agonist-induced, TRAF6-dependent stabilization. 1545 87

Somatostatin is a polypeptide hormone acting as an inhibitor of pituitary, pancreatic, and gastrointestinal secretion through specific membrane receptors of which five subtypes have been cloned (sst(1-5)). Somatostatin analogs are used in the clinic to treat patients with excessive hormone production due to a neuroendocrine tumor. The aim of this study was to investigate the biological activity of three new somatostatin receptor subtype selective analogs (BIM-23926, sst(1)-selective; BIM-23120, sst(2)-selective; and BIM-23206, sst(5)-selective) in the human neuroendocrine tumor cell line, BON-1, which expresses sst(1), sst(2), and sst(5) natively. Somatostatin-14 and octreotide were used as reference substances. Forskolin-induced cAMP accumulation and chromogranin A (CgA) secretion were inhibited by BIM-23120, BIM-23206, and somatostatin-14 in a dose-dependent manner. Cholecystokinin (CCK-8) stimulated activation of mitogen-activated protein (MAP) kinase was inhibited by BIM-23120 and BIM-23206, while BIM-23926 stimulated the activity. Selective BIM analogs showed a more efficient inhibitory effect on cAMP accumulation, CgA secretion, and MAP kinase activity than octreotide in BON-1 cells. This may be explained by the differences in affinity of the ligand to the receptor or by interaction between different sst subtypes. We conclude that increasing knowledge about sst physiology and expression in malignant disease indicates a need for new analogs that can be incorporated into the therapeutic arsenal.
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PMID:Subtype selective interactions of somatostatin and somatostatin analogs with sst1, sst2, and sst5 in BON-1 cells. 1545 57


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