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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

c-Jun transcriptional activity is augmented by expression of oncogenic Ras and Raf proteins. This study demonstrates a direct correlation between Ras transforming activity and c-Jun activation, supporting an important role for c-Jun in transformation by Ras. Since we observed that Ras activated c-Jun transcriptional activity by increasing phosphorylation of the c-Jun activation domain at residues Ser-63/Ser-73 and that oncogenic Ras proteins activated extracellular signal-regulated protein kinases (ERK1 and ERK2) (also known as mitogen-activated protein kinases), we evaluated the possibility that ERKs were directly responsible for c-Jun activation. Coexpression of wild-type ERKs with oncogenic Ras proteins potentiated, while kinase-defective ERKs inhibited, Ras-induced transcriptional activation from the Ras-responsive element (Ets-1/AP-1) present in the NVL-3 enhancer and the serum-response element in the c-fos promoter. In contrast, coexpression of either wild-type or kinase-defective ERKs inhibited Ras and Raf activation of c-Jun transcriptional activity. Thus, although activation of both ERK and c-Jun are downstream consequences of activation of the Ras signal transduction pathway, our results suggest that Ras-induced c-Jun phosphorylation and transcriptional activation are not a direct consequence of ERK1 and ERK2 activation.
...
PMID:Oncogenic Ras activates c-Jun via a separate pathway from the activation of extracellular signal-regulated kinases. 801 10

The simian virus 40 small tumor antigen (small t) specifically interacts with protein phosphatase type 2A (PP2A) in vivo and alters its catalytic activity in vitro. Among the substrates for PP2A in vitro are the activated forms of MEK and ERK kinases. Dephosphorylation of the activating phosphorylation sites on MEK and ERKs by PP2A in vitro results in a decrease in their respective kinase activities. Recently, it has been shown that overexpression of small t in CV-1 cells results in an inhibition of PP2A activity toward MEK and ERK2 and a constitutive upregulation of MEK and ERK2 activity. Previously, we have observed that overexpression of either ERK1, MEK1, or a constitutively active truncated form of c-Raf-1 (BXB) is insufficient to activate AP-1 in REF52 fibroblasts. We therefore examined whether overexpression of small t either alone or in conjunction with ERK1, MEK1, or BXB could activate AP-1. We found that coexpression of small t and either ERK1, MEK1, or BXB resulted in an increase in AP-1 activity, whereas expression of either small t or any of the kinases alone did not have any effect. Similarly, coexpression of small t and ERK1 activated serum response element-regulated promoters. Coexpression of kinase-deficient mutants of ERK1 and ERK2 inhibited the activation of AP-1 caused by expression of small t and either MEK1 or BXB. Coexpression of an interfering MEK, which inhibited AP-1 activation by small t and BXB, did not inhibit the activation of AP-1 caused by small t and ERK1. In contrast to REF52 cells, we observed that overexpression of either small or ERK1 alone in CV-1 cells was sufficient to stimulate AP-1 activity and that this stimulation was not enhanced by expression of small t and ERK1 together. These results show that the effects of small t on immediate-early gene expression depend on the cell type examined and suggest that the mitogen-activated protein kinase activation pathway is distinctly regulated in different cell types.
...
PMID:Simian virus 40 small t antigen cooperates with mitogen-activated kinases to stimulate AP-1 activity. 806 56

Ras proteins exert their mitogenic and oncogenic effects through activation of downstream protein kinases. An important question is how Ras-generated signals reach the nucleus to activate downstream target genes. AP-1, a heterodimeric complex of Jun and Fos proteins, which activates mitogen-inducible genes, is a major nuclear target of Ras. Ras can stimulate AP-1 activity by inducing c-fos transcription, a process which is probably mediated by the ERK1 and -2 mitogen-activated protein (MAP) kinases, which phosphorylate the transcription factor Elk-1/TCF. Besides inducing transcription from fos and jun genes, mitogens and Ras proteins enhance AP-1 activity through phosphorylation of c-Jun. Phosphorylation of the c-Jun activation domain leads to c-jun induction through an autoregulatory loop. Ras- and ultra-violet-responsive protein kinases that phosphorylate c-Jun on serine residues at positions 63 and 73 and stimulate its transcriptional activity have been identified. These proline-directed kinases, termed JNKs, are novel MAP kinases. It is not clear, however, whether c-Jun is the only recipient and JNK the only transducer of the Ras signal to AP-1 proteins. A short sequence surrounding the major JNK phosphorylation site of c-Jun is conserved in c-Fos and is part of its activation domain, suggesting that c-Fos may be similarly regulated. Here we show that Ras does indeed augment the transcriptional activity of c-Fos through phosphorylation at Thr 232, the homologue of Ser 73 of c-Jun. However, this is mediated by a novel Ras- and mitogen-responsive proline-directed protein kinase that is different from JNKs and ERKs. Therefore, at least three types of proline-directed kinases transmit Ras- and mitogen-generated signals to the transcriptional machinery.
...
PMID:c-Fos transcriptional activity stimulated by H-Ras-activated protein kinase distinct from JNK and ERK. 807 47

Rab4, a low-molecular-mass GTP-binding protein, is associated with vesicles containing Glut 4 in adipocytes. Following insulin stimulation, the translocation of Glut 4 to the plasma membrane is associated with the movement of Rab4 to the cytosol. The same modifications are induced by the phosphatase inhibitor, okadaic acid. To establish a possible role for phosphorylation in Rab4 cycling, we searched for insulin-stimulated cytosolic kinase(s) which could phosphorylate Rab4. In 3T3-L1 adipocytes, insulin induced a rapid and transient activation of cytosolic kinase(s), which phosphorylated Rab4 in vitro. At least part of the Rab4 phosphorylation can be accounted for by ERK (extracellular-signal-regulated kinases) since immunopurified ERK1 from insulin-stimulated cells phosphorylated Rab4 with a comparable time-course. Both with cytosolic extracts and immunopurified ERK1, only serine residues were phosphorylated on Rab4. The phosphorylation site was localized in the C-terminus of the molecule, and occurred very probably on Ser196. These results indicate that Rab4 is an in vitro substrate for ERK, and suggest that the insulin-induced movement of Rab4 from the Glut-4-containing vesicles to the cytosol could result from phosphorylation of Rab4 by ERK.
...
PMID:Rab4 is phosphorylated by the insulin-activated extracellular-signal-regulated kinase ERK1. 811 21

The protein kinase cascade Raf-MAPKK/MEK-MAPK/ERK connects protein tyrosine kinase receptors in the membrane with control of transcription factor activity in the nucleus. We have examined whether Raf is obligatory for activation of this cascade and whether this signaling pathway is relevant to transformation. By use of transient assays with epitope-tagged ERK-1 cDNA and a dominant inhibitory mutant of Raf-1 we found that serum and 12-O-tetradecanoylphorbol-13-acetate as well as representatives of three classes of oncogenes (protein tyrosine kinases abl/src, Ras, and protein serine/threonine kinases mos/cot) were all Raf-dependent for stimulation of MAPK. All of the MAPK stimulating oncogenes were also activators of Raf kinase as judged by shift induction. It thus appears that there is little or no redundancy in pathways used by growth regulators for activation of MAPK/ERK. Furthermore, the ability to stimulate MAPK/ERK appears to be critical for transformation by oncogenic Raf-1 and ERK-1 and -2 synergized with v-raf in a focus induction assay on NIH3T3 cells and kinase dead mutants of ERK-2 were inhibitory. Raf/ERK synergism was also observed in transcriptional transactivation of the oncogene-response element in the polyoma enhancer. We conclude that this Raf signaling pathway, which connects to many upstream activators and downstream effectors, is essential for transformation by most oncogenes.
...
PMID:Mitogen-activated protein kinase/extracellular signal-regulated protein kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13-acetate requires Raf and is necessary for transformation. 812 67

The present study revealed that the pineal gland expressed basic fibroblast growth factor (bFGF) and FGF-receptor 1 (FGFR1/flg), suggesting that bFGF in the pineal gland acts in an autocrine or paracrine manner, which is mediated by FGFR1/flg. The present study also examined gene expression of the extracellular signal-regulated kinase (ERK) family (ERK1-3) which may be intracellular signal mediators of growth factors. ERK1 [mitogen-activated protein kinase (MAP-kinase)] was strongly expressed throughout the pineal gland, while expression of ERK2 and ERK3 was not found. These findings suggest the presence of a signal pathway from bFGF to ERK1 via FGFR1/flg in the pineal gland.
...
PMID:Growth factors and extracellular signal-regulated kinases (mitogen-activated protein kinase) in the rat pineal gland. 812 4

The role of ERK-1 and ERK-2 in wild-type (wt) Ha-Ras, phorbol 12-myristate 13-acetate (PMA), and serum-induced AP-1 activity was studied. Microinjection of ERK-specific substrate peptides inhibited the induction of AP-1 activity by all three stimuli, whereas a control peptide had no effect. By using eukaryotic expression constructs encoding wt ERK-1 and kinase-deficient mutants of ERKs 1 and 2, it was found that ERK-1 and ERK-2 activities are required for AP-1 activation stimulated by either wt Ha-Ras, PMA, or serum. Overexpression of ERK-1 augmented wt Ha-Ras stimulation of AP-1, while having no effect upon PMA or serum stimulation. Overexpression of either kinase-deficient ERK-1 or kinase-deficient ERK-2 partially inhibited AP-1 activation by wt Ha-Ras but had no effect on PMA or serum-induced activation. Coexpression of both interfering mutants abolished AP-1 induction by wt Ha-Ras, PMA, or serum. We conclude that ERKs are necessary components in the pathway leading to the activation of AP-1 stimulated by these agents.
...
PMID:A requirement for extracellular signal-regulated kinase (ERK) function in the activation of AP-1 by Ha-Ras, phorbol 12-myristate 13-acetate, and serum. 817 Sep 99

Interaction with SV40 small tumor antigen (small t) compromised the ability of multimeric protein phosphatase 2A to inactivate the mitogen-activated protein kinase ERK1 and the mitogen-activated protein kinase kinase MEK1. Transient expression of small t in CV-1 cells activated MEK and ERK but did not affect Raf activity. Small t stimulated the growth of quiescent CV-1 cells almost as effectively as did serum. Coexpression of kinase-deficient ERK2 blocked most, but not all, of the proliferation caused by small t. Activation of the mitogen-activated protein kinase pathway and stimulation of cell growth were dependent on the interaction of small t with protein phosphatase 2A. These findings indicate that SV40 small t is capable of inducing cell growth through blockade of protein phosphatase and deregulation of the mitogen-activated protein kinase cascade.
...
PMID:The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. 825 25

RCR cells are NRK clones in which Raf-1 production is blocked by the expression of an antisense RNA, and consequently they are refractory to transformation by various oncogenes. In RCR cells, MAP kinases (ERK1 and ERK2) were activated to an extent and in a time course similar to those of the original NRK cells, irrespective of whether the stimulus was oncogenic or non-oncogenic. Moreover, there was no significant elevation of ERK activities in oncogene-transformed NRK cells. These results indicate that Raf-1 kinase is not the major upstream activator of ERK's in NRK cells and that neither ERK1 nor ERK2 are likely to mediate oncogenic signals from Raf-1 kinase.
...
PMID:Raf-1 is not a major upstream regulator of MAP kinases in rat fibroblasts. 826 40

Raf-1 is a serine/threonine kinase which is essential in cell growth and differentiation. Tyrosine kinase oncogenes and receptors and p21ras can activate Raf-1, and recent studies have suggested that Raf-1 functions upstream of MEK (MAP/ERK kinase), which phosphorylates and activates ERK. To determine whether or not Raf-1 directly activates MEK, we developed an in vitro assay with purified recombinant proteins. Epitope-tagged versions of Raf-1 and MEK and kinase-inactive mutants of each protein were expressed in Sf9 cells, and ERK1 was purified as a glutathione S-transferase fusion protein from bacteria. Raf-1 purified from Sf9 cells which had been coinfected with v-src or v-ras was able to phosphorylate kinase-active and kinase-inactive MEK. A kinase-inactive version of Raf-1 purified from cells that had been coinfected with v-src or v-ras was not able to phosphorylate MEK. Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. We conclude that MEK is a direct substrate of Raf-1 and that the activation of MEK by Raf-1 is due to phosphorylation by Raf-1, which is sufficient for MEK activation. We also tested the ability of protein kinase C to activate Raf-1 and found that, although protein kinase C phosphorylation of Raf-1 was able to stimulate its autokinase activity, it did not stimulate its ability to phosphorylate MEK.
...
PMID:Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro. 841 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---