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

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

Adenosine is arguably the most potent and widespread presynaptic modulator in the CNS, yet adenosine receptor signal transduction pathways remain unresolved. Here, we demonstrate a novel mechanism in which adenosine A1 receptor stimulation leads to p38 mitogen-activated protein kinase (MAPK) activation and contributes to the inhibition of synaptic transmission. Western blot analysis indicated that selective A1 receptor activation [with N6-cyclopentyladenosine (CPA)] resulted in rapid increases in phosphorylated p38 (phospho-p38) MAPK immunoreactivity in membrane fractions, and decreases in phospho-p38 MAPK in cytosolic fractions. Immunoprecipitation with a phospho-p38 MAPK antibody revealed constitutive association of this phosphoprotein with adenosine A1 receptors. Phospho-p38 MAPK activation by A1 receptor stimulation induced translocation of PP2a (protein phosphatase 2a) to the membrane. We then examined the actions of p38 MAPK activation in A1 receptor-mediated synaptic inhibition. Excitatory postsynaptic field potentials evoked in area CA1 of the rat hippocampus markedly decreased in response to adenosine (10 microM), the A1 receptor agonist CPA (40 nM), or a 5 min exposure to hypoxia. These inhibitory responses were mediated by A1 receptor activation because the selective antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (100 nM) prevented them. In agreement with the biochemical analysis, the selective p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] (25 microM) blocked the inhibitory actions of A1 receptor activation, whereas both the inactive analog SB202474 [4-ethyl-2-(p-methoxyphenyl)-5-(4'-pyridyl)-1H-imidazole] (25 microM) and the ERK 1/2 (extracellular signal-regulated kinase 1/2) MAPK inhibitor PD98059 [2'-amino-3'-methoxyflavone] (50 microM) were ineffective. In contrast, the p38 MAPK inhibitors did not inhibit GABA(B)-mediated synaptic depression. These data suggest A1 receptor-mediated p38 MAPK activation is a crucial step underlying the presynaptic inhibitory effect of adenosine on CA3-CA1 synaptic transmission.
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PMID:p38 mitogen-activated protein kinase contributes to adenosine A1 receptor-mediated synaptic depression in area CA1 of the rat hippocampus. 1713 4

Pax-6 is an evolutionarily conserved transcription factor and acts high up in the regulatory hierarchy controlling eye and brain development in humans, mice, zebrafish, and Drosophila. Previous studies have shown that Pax-6 is a phosphoprotein, and its phosphorylation by ERK, p38, and homeodomain-interacting protein kinase 2 greatly enhances its transactivation activity. However, the protein phosphatases responsible for the dephosphorylation of Pax-6 remain unknown. Here, we present both in vitro and in vivo evidence to show that protein serine/threonine phosphatase-1 is a major phosphatase that directly dephosphorylates Pax-6. First, purified protein phosphatase-1 directly dephosphorylates Pax-6 in vitro. Second, immunoprecipitation-linked Western blot revealed that both protein phosphatase-1alpha and protein phosphatase-1beta interact with Pax-6. Third, overexpression of protein phosphatase-1 in human lens epithelial cells leads to dephosphorylation of Pax-6. Finally, inhibition of protein phosphatase-1 activity by calyculin A or knockdown of protein phosphatase-1alpha and protein phosphatase-1beta by RNA interference leads to enhanced phosphorylation of Pax-6. Moreover, our results also demonstrate that dephosphorylation of Pax-6 by protein phosphatase-1 significantly modulates its function in regulating expression of both exogenous and endogenous genes. These results demonstrate that protein phosphatase 1 acts as a major phosphatase to dephosphorylate Pax-6 and modulate its function.
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PMID:Protein phosphatase-1 modulates the function of Pax-6, a transcription factor controlling brain and eye development. 1737 6

Induction of G(2)/M phase transition in mitotic and meiotic cell cycles requires activation by phosphorylation of the protein phosphatase Cdc25. Although Cdc2/cyclin B and polo-like kinase (PLK) can phosphorylate and activate Cdc25 in vitro, phosphorylation by these two kinases is insufficient to account for Cdc25 activation during M phase induction. Here we demonstrate that p42 MAP kinase (MAPK), the Xenopus ortholog of ERK2, is a major Cdc25 phosphorylating kinase in extracts of M phase-arrested Xenopus eggs. In Xenopus oocytes, p42 MAPK interacts with hypophosphorylated Cdc25 before meiotic induction. During meiotic induction, p42 MAPK phosphorylates Cdc25 at T48, T138, and S205, increasing Cdc25's phosphatase activity. In a mammalian cell line, ERK1/2 interacts with Cdc25C in interphase and phosphorylates Cdc25C at T48 in mitosis. Inhibition of ERK activation partially inhibits T48 phosphorylation, Cdc25C activation, and mitotic induction. These findings demonstrate that ERK-MAP kinases are directly involved in activating Cdc25 during the G(2)/M transition.
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PMID:Regulation of Cdc25C by ERK-MAP kinases during the G2/M transition. 1738 81

Ser910 of FAK (focal adhesion kinase) was phosphorylated in fibroblasts treated with the phorbol ester PMA and dephosphorylated by PP1d (protein phosphatase 1d), as indicated by shRNA (small-hairpin RNA) gene silencing. Ser910 of FAK was reported previously to be an ERK (extracellular-signal-regulated kinase) 1/2 target in cells treated with phorbol esters. In contrast, various approaches, including the use of the MEK (mitogen-activated protein kinase/ERK kinase) inhibitors UO126 and CI-1040 to inhibit ERK1/2 pointed to the involvement of ERK5. This hypothesis was confirmed by: (i) shRNA ERK5 gene silencing, which resulted in complete pSer910 loss in non-stimulated and PMA-stimulated cells; (ii) direct phosphorylation of recombinant FAK by ERK5; and (iii) ERK5 activation by PMA. PMA stimulation and ERK5 silencing in MDA-MB 231 and MDA-MB 361 breast cancer cells indicated Ser910 targeting by ERK5 also in these cells. Given the proximity of Ser910 to the FAT (focal adhesion targeting) regulatory domain of FAK, cell proliferation and morphology were investigated in FAK-/- cells expressing S910A mutant FAK. The cell growth rate decreased and exposure to PMA induced peculiar morphological changes in cells expressing S910A, with respect to wild-type FAK, suggesting a role for Ser910 in these processes. The present study indicates, for the first time, the phosphorylation of Ser910 of FAK by ERK5 and its dephosphorylation by PP1d, and suggested a role for Ser910 in the control of cell shape and proliferation.
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PMID:Targeting of FAK Ser910 by ERK5 and PP1delta in non-stimulated and phorbol ester-stimulated cells. 1769 50

We used Western blot analysis to examine the effect of dietary K intake on the expression of serine/threonine protein phosphatase in the kidney. K restriction significantly decreased the expression of catalytic subunit of protein phosphatase (PP)2B but increased the expression of PP2B regulatory subunit in both rat and mouse kidney. However, K depletion did not affect the expression of PP1 and PP2A. Treatment of M-1 cells, mouse cortical collecting duct (CCD) cells, or 293T cells with glucose oxidase (GO), which generates superoxide anions through glucose metabolism, mimicked the effect of K restriction on PP2B expression and significantly decreased expression of PP2B catalytic subunits. However, GO treatment increased expression of regulatory subunit of PP2B and had no effect on expression of PP1, PP2A, and protein tyrosine phosphatase 1D. Moreover, deletion of gp91-containing NADPH oxidase abolished the effect of K depletion on PP2B. Thus superoxide anions or related products may mediate the inhibitory effect of K restriction on the expression of PP2B catalytic subunit. We also used patch-clamp technique to study the effect of inhibiting PP2B on renal outer medullary K (ROMK) channels in the CCD. Application of cyclosporin A or FK506, inhibitors of PP2B, significantly decreased ROMK channels, and the effect of PP2B inhibitors was abolished by blocking p38 mitogen-activated protein kinase (MAPK) and ERK. Furthermore, Western blot demonstrated that inhibition of PP2B with cyclosporin A or small interfering RNA increased the phosphorylation of ERK and p38 MAPK. We conclude that K restriction suppresses the expression of PP2B catalytic subunits and that inhibition of PP2B decreases ROMK channel activity through stimulation of MAPK in the CCD.
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PMID:K restriction inhibits protein phosphatase 2B (PP2B) and suppression of PP2B decreases ROMK channel activity in the CCD. 1818 75

The mammalian amino acid response (AAR) pathway is up-regulated by protein or amino acid depletion. This pathway involves detection of uncharged tRNA by the GCN2 kinase, phosphorylation of the translation initiation factor eIF2alpha (eukaryotic initiation factor 2alpha), and, through subsequent translational control, enhanced de novo synthesis of the transcription factor ATF4. The present studies demonstrate that inhibition of MEK activation in HepG2 human hepatoma cells by PD98059 or U0126 blocked the increased phosphorylation of eIF2alpha and ATF4 synthesis triggered by amino acid limitation, showing that the AAR requires activation of the MEK-ERK pathway. Inhibitors of the JNK or p38 MAPK pathways were ineffective. Consequently, inhibition of MEK activation blocked transcriptional induction of ATF4 target genes, but the induction was rescued by overexpression of ATF4 protein. Furthermore, the enhanced ERK phosphorylation following amino acid deprivation required GCN2 kinase activity and eIF2alpha phosphorylation. Inhibition of protein phosphatase 1 action on phospho-eIF2alpha by knockdown of GADD34 did not block the sensitivity to PD98059, suggesting that MEK functions to enhance GCN2-dependent eIF2alpha phosphorylation rather than suppressing dephosphorylation. Collectively, these results document a critical interdependence between the MEK-ERK MAPK signaling pathway and the amino acid stress-activated pathway.
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PMID:MEK signaling is required for phosphorylation of eIF2alpha following amino acid limitation of HepG2 human hepatoma cells. 1828 93

PTEN is a dual lipid and protein phosphatase that antagonizes PI3K as well as other signaling pathways and regulates cellular survival and growth. However, its potential role in cardiac ischemia/reperfusion injury remains unknown. We established a transgenic mouse model with inducible and cardiac specific deletion of Pten gene (Pten(CKO)) in adult heart via tamoxifen dependent Cre-loxP mediated DNA recombination. 3 weeks after tamoxifen induced PTEN inactivation, elevated PI3K activity was observed in the Pten(CKO) hearts as determined from downstream AKT signaling. No significant differences in cardiac function as well as chamber size were observed between Pten(CKO) and Control animals based on echocardiography. In response to 30 min ischemia followed by 120 min reperfusion in Langendorff preparations, Pten(CKO) hearts developed significantly better function recovery than Control animals. At 60 min post reperfusion, the recovery of LVDP reached 77.9% of pre-ischemia basal in Pten(CKO) hearts vs 44.2% of Control (p<0.01). Consistent with the observed functional improvement, TTC staining revealed a significant reduction in infarct size in Pten(CKO) hearts compared with Control (24.2% vs 39.7%, p<0.05). Pten(CKO) hearts had significantly fewer apoptosis positive cardiomyocytes after I/R injury as identified by TUNEL staining. Furthermore, ERK activity and BCL-2 expression were not affected at basal but became significantly higher after ischemia/reperfusion in Pten(CKO) hearts. These data indicate that PTEN may play a role in ischemia/reperfusion injury by inhibiting anti-apoptotic survival signals. Inhibiting PTEN may serve as a potential approach to exert cardiac protection against ischemia reperfusion injury.
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PMID:Inducible and cardiac specific PTEN inactivation protects ischemia/reperfusion injury. 1903 62

Three different genes of catalytic subunit A of the Ca(2+)-dependent serine/threonine protein phosphatase calcineurin (CaN) are encoded in the human genome forming heterodimers with regulatory subunit B. Even though physiological roles of CaN have been investigated extensively, less is known about the specific functions of the different catalytic isoforms. In this study, all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time. Comparative kinetic analysis of the dephosphorylation of five specific CaN substrates provided evidence that the distinct isoforms of the catalytic subunit confer substrate specificities to the holoenzymes. CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively. CaN gamma exhibits the highest k(cat)/K(m) value for DARPP-32, whereas the catalytic efficiencies for the dephosphorylation of NFAT and RII peptide were 3- and 5-fold lower, respectively, when compared with the other isoforms. Elk-1 and NFAT reporter gene activity measurements revealed even more pronounced substrate preferences of CaNA isoforms. Moreover, kinetic analysis demonstrated that CaN beta exhibits for all tested protein substrates the lowest K(m) values. Enzymatic characterization of the CaN beta(P14G/P18G) variant as well as the N-terminal truncated form CaN beta(22-524) revealed that the proline-rich sequence of CaN beta is involved in substrate recognition. CaN beta(22-524) exhibits an at least 4-fold decreased substrate affinity and a 5-fold increased turnover number. Since this study demonstrates that all CaN isoforms display the same cytoplasmic subcellular distribution and are expressed in each tested cell line, differences in substrate specificities may determine specific physiological functions of the distinct isoforms.
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PMID:The proline-rich N-terminal sequence of calcineurin Abeta determines substrate binding. 1915 38

A tumor suppressor gene at 10q23.3, designated PTEN, encoding a dual-specificity phosphatase with lipid and protein phosphatase activity, has been shown to play a pivotal role in the pathogenesis of a variety of human cancers. A frequent loss of heterozygosity (LOH) at 10q is found in melanoma; however, little is known about the role of PTEN in the pathogenesis of a primary malignant melanoma derived from ovarian mature cystic teratoma, which is an extremely rare melanoma. This study examined the genetic alterations involved in the mitogen-activated protein kinase and phosphatidylinositol 3 kinase pathways in an ovarian malignant melanoma. A LOH analysis revealed hemizygous deletion around and in the PTEN gene not only in the ovarian melanoma but also in a mature cystic teratoma. Another case of ovarian mature cystic teratomas in the absence of melanoma also showed allelic loss of the PTEN region. To date, mutations of BRAF, NRAS, and KIT genes have been reported in malignant melanomas. In the present study, D816H and K558E mutations of the KIT gene were revealed in the melanoma arising from a mature cystic teratoma, but not in a mature cystic teratoma. No mutations of the BRAF and NRAS genes were found in the melanoma. These results indicate that LOH of the PTEN region is one of the molecular alterations of an ovarian mature cystic teratoma and a KIT mutation is an additional promotional event associated with the oncogenesis of a melanoma arising from an ovarian mature cystic teratoma.
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PMID:Mutations of the KIT gene and loss of heterozygosity of the PTEN region in a primary malignant melanoma arising from a mature cystic teratoma of the ovary. 1926 28

Protein scaffolds have emerged as important regulators of MAPK cascades, facilitating kinase activation and providing crucial spatio/temporal control to their signaling outputs. Using a proteomics approach to compare the binding partners of the two mammalian KSR scaffolds, we find that both KSR1 and KSR2 interact with the kinase components of the ERK cascade and have a common function in promoting RTK-mediated ERK signaling. Strikingly, we find that the protein phosphatase calcineurin selectively interacts with KSR2 and that KSR2 uniquely contributes to Ca2+-mediated ERK signaling. Calcineurin dephosphorylates KSR2 on specific sites in response to Ca2+ signals, thus regulating KSR2 localization and activity. Moreover, we find that depletion of endogenous KSR2 impairs Ca2+-mediated ERK activation and ERK-dependent signaling responses in INS1 pancreatic beta-cells and NG108 neuroblastoma cells. These findings identify KSR2 as a Ca2+-regulated ERK scaffold and reveal a new mechanism whereby Ca2+ impacts Ras to ERK pathway signaling.
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PMID:KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals. 1956 Apr 18


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