Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extracellular signal-regulated protein kinases (ERKs) are proline-directed, serine/threonine kinases that regulate a variety of cellular functions, including proliferation, differentiation, and plasticity. In the present report, we provide evidence that ERK2 and phosphatidylinositol-specific phospholipase C (PLC)-beta and -gamma isozymes interact in the rat hippocampal formation. We found that anti-PLC-beta1a, -beta2, -beta4, -gamma1 and -gamma2, but not -beta3, immune complexes isolated from rat hippocampal formation postnuclear fractions contain anti-ERK2 immunoreactivity. Further, we show that PLC catalytic activity is associated with anti-ERK2 immunoprecipitates isolated from the hippocampal formation, and that the amount of enzyme activity is significantly increased following fear-conditioned learning. The observed interactions may be mediated by consensus sequences conforming to an ERK2 docking site, termed a D-domain, that we identified in PLC-beta1a, -beta2, -beta4 -gamma1 and -gamma2. Based on these results, we propose that PLC-beta and PLC-gamma isozymes form signaling complexes with ERK2 in rat brain, and these complexes play critical roles in learning and memory, as well as a variety of other neuronal functions.
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PMID:Fear conditioning is associated with altered integration of PLC and ERK signaling in the hippocampus. 1558 71

Although hypoxia and transforming growth factor-beta (TGF-beta) inhibit differentiation of adipocytes from preadipocytes and bone marrow-derived cells in several species, the relationship between hypoxia and TGF-beta signaling in adipocytogenesis is unknown. In this study, we evaluated the mechanisms of inhibition of adipocyte differentiation by hypoxia and TGF-beta in human and murine marrow stromal cells (MSCs) and the role of TGF-beta/Smad signaling in the inhibition of adipocytogenesis by hypoxia. Both hypoxia-mimetic deferoxamine mesylate (DFO) and TGF-beta1 inhibited adipocyte differentiation (1.0% versus the control at 15 microm DFO and 1.4% versus the control at 1 ng/ml TGF-beta1) and adipocyte gene expression (peroxisome proliferator-activated receptor-gamma2 and lipoprotein lipase) in human MSCs after 21 days of treatment. Hypoxia (2% O(2)) and DFO (but not TGF-beta1) increased hypoxia-inducible factor-1alpha as shown by Western blotting. Macroarrays and Western and Northern blot analyses showed that hypoxia activated the TGF-beta/Smad signaling pathway and that both hypoxia and TGF-beta1 modulated adipocyte differentiation pathways such as the insulin-, peroxisome proliferator-activated receptor-gamma-, phosphatidylinositol 3-kinase-, and MAPK-associated signaling pathways. Studies with mouse marrow stromal cell lines derived from Smad3(+/+) or Smad3(-/-) mice revealed that the TGF-beta type I receptor (ALK-5) and its intracellular signaling molecule Smad3 were necessary for the inhibition of adipocyte differentiation by both TGF-beta and hypoxia-mimetic DFO. Thus, the TGF-beta/Smad signaling pathway is required for hypoxia-mediated inhibition of adipocyte differentiation in MSCs.
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PMID:Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires transforming growth factor-beta/Smad3 signaling. 1584 40

Overexpression of epidermal growth factor receptor (EGFR) was shown for the majority of squamous cell carcinomas. The EGFR expression correlates to tumour size, stage and cytoplasmic accumulation of the laminin-5 gamma2 chain (Ln-5/gamma2), which is known as a marker of invading tumour cells. There is only limited knowledge if and how EGFR signalling pathways are important for invasion-associated processes and for the regulation of Ln-5/gamma2. Therefore the distribution of phosphorylated Erk1/2, p38 MAPK and Akt was immunohistochemically defined in oral squamous cell carcinoma (OSCC) of different histological grade and compared to histological criteria of invasion and cytoplasmic Ln-5/gamma2 deposition. With raising histological grade, there is a slight increase in nuclear pErk1/2-stained tumour cells (P=0.398) and a loss of nuclear (P=0.593) and increased cytoplasmic staining (P=0.144) of pAkt mainly in invading OSCC cells. Nuclear pp38 MAPK could only be sporadically detected in few cases. In case of pErk1/2 and pAkt, only a partial co-localisation could be revealed in cases with abundant kinases and Ln-5/gamma2. Among the investigated kinases, only pAkt shows a relation to histological grade and invasion in OSCC. pErk1/2, pp38 MAPK and pAkt do not represent a direct link between EGFR and Ln-5 synthesis. Therefore, enhanced Ln-5/gamma2 may be a secondary phenomenon of EGFR-induced tumour cell proliferation and dissemination.
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PMID:Analysis of activated EGFR signalling pathways and their relation to laminin-5 gamma2 chain expression in oral squamous cell carcinoma (OSCC). 1605 24

Assembly of a signaling complex around the transmembrane adapter LAT is essential for the transmission of T-cell receptor (TCR)-mediated signaling. However, a LAT-like molecule responsible for the initial activation events in B-cell receptor (BCR) signaling has not yet been identified. Here, we show that LIME is a transmembrane adaptor required for BCR-mediated B-cell activation. LIME was found to be expressed in mouse splenic B cells. Upon BCR cross-linking, LIME was tyrosine phosphorylated by Lyn and associated with Lyn, Grb2, PLC-gamma2, and PI3K. Reduction of LIME expression by the introduction of siRNA resulted in the disruption of BCR-mediated activation of MAPK, calcium flux, NF-AT, PI3K, and NF-kappaB. Taken together, these results establish that LIME is an essential transmembrane adaptor linking BCR ligation to the downstream signaling events that lead to B-cell activation.
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PMID:LIME acts as a transmembrane adapter mediating BCR-dependent B-cell activation. 1624 87

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a central role in whole body metabolism by regulating adipocyte differentiation and energy storage. Recently, however, PPAR-gamma has also been demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. As we have previously shown that BAY 11-7085-induced synovial fibroblast apoptosis is prevented by PPAR-gamma agonist 15d-PGJ2; the expression of PPAR-gamma in these cells was studied. Both PPAR-gamma1 and PPAR-gamma2 isoforms were cloned from synovial fibroblast RNA, but only PPAR-gamma1 was detected by Western blot, showing constitutive nuclear expression. Within minutes of BAY 11-7085 treatment, a PPAR-gamma1-specific band was shifted into a form of higher mobility, suggesting dephosphorylation, as confirmed by phosphatase treatment of cell extracts. Of interest, BAY 11-7085-induced PPAR-gamma1 dephosphorylation was followed by PARP and caspase-8 cleavage as well as by PPAR-gamma1 protein degradation. PPAR-gamma1 dephosphorylation was followed by the loss of PPAR-DNA binding activity ubiquitously present in synovial fibroblast nuclear extracts. Unlike the phosphorylated form, dephosphorylated PPAR-gamma1 was found in insoluble membrane cell fraction and was not ubiquitinated before degradation. PPAR-gamma1 dephosphorylation coincided with ERK1/2 phosphorylation that accompanies BAY 11-7085-induced synovial fibroblasts apoptosis. 15d-PGJ2, PGD2, and partially UO126, down-regulated ERK1/2 phosphorylation, protected cells from BAY 11-7085-induced apoptosis, and reversed both PPAR-gamma dephosphorylation and degradation. Furthermore, PPAR-gamma antagonist BADGE induced PPAR-gamma1 degradation, ERK1/2 phosphorylation, and synovial fibroblasts apoptosis. The results presented suggest an anti-apoptotic role for PPAR-gamma1 in synovial fibroblasts. Since apoptotic marker PARP is cleaved after PPAR-gamma1 dephosphorylation but before PPAR-gamma1 degradation, dephosphorylation event might be enough to mediate BAY 11-7085-induced apoptosis in synovial fibroblasts.
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PMID:Peroxisome proliferator-activated receptor-gamma1 is dephosphorylated and degraded during BAY 11-7085-induced synovial fibroblast apoptosis. 1676 31

Altered function of gamma-aminobutyric acid type A receptors (GABA(A)Rs) in dentate granule cells of the hippocampus has been associated with temporal lobe epilepsy (TLE) in humans and in animal models of TLE. Such altered receptor function (including increased inhibition by zinc and lack of modulation by benzodiazepines) is related, in part, to changes in the mRNA levels of certain GABA(A)R subunits, including alpha4, and may play a role in epileptogenesis. The majority of GABA(A)Rs that contain alpha4 subunits are extra-synaptic due to lack of the gamma2 subunit and presence of delta. However, it has been hypothesized that seizure activity may result in expression of synaptic receptors with altered properties driven by an increased pool of alpha4 subunits. Results of our previous work suggests that signaling via protein kinase C (PKC) and early growth response factor 3 (Egr3) is the plasticity trigger for aberrant alpha4 subunit gene (GABRA4) expression after status epilepticus. We now report that brain derived neurotrophic factor (BDNF) is the endogenous signal that induces Egr3 expression via a PKC/MAPK-dependent pathway. Taken together with the fact that blockade of tyrosine kinase (Trk) neurotrophin receptors reduces basal GABRA4 promoter activity by 50%, our findings support a role for BDNF as the mediator of Egr3-induced GABRA4 regulation in developing neurons and epilepsy and, moreover, suggest that BDNF may alter inhibitory processing in the brain by regulating the balance between phasic and tonic inhibition.
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PMID:Brain-derived neurotrophic factor (BDNF)-induced synthesis of early growth response factor 3 (Egr3) controls the levels of type A GABA receptor alpha 4 subunits in hippocampal neurons. 1690 9

Preadipocyte factor 1 (Pref-1) is found in preadipocytes but is absent in adipocytes. Pref-1 is made as a transmembrane protein but is cleaved to generate a biologically active soluble form. Although Pref-1 inhibition of adipogenesis has been well studied in vitro and in vivo, the signaling pathway for Pref-1 is not known. Here, by using purified soluble Pref-1 in Pref-1 null mouse embryo fibroblasts (MEF), we show that Pref-1 increases MEK/extracellular signal-regulated kinase (ERK) phosphorylation in a time- and dose-dependent manner. Compared to wild-type MEF, differentiation of Pref-1 null MEF into adipocytes is enhanced, as judged by lipid accumulation and adipocyte marker expression. Both wild-type and Pref-1 null MEF show a transient burst of ERK phosphorylation upon addition of adipogenic agents. Wild-type MEF show a significant, albeit lower, second increase in ERK phosphorylation peaking at day 2. This ERK phosphorylation, corresponding to Pref-1 abundance, is absent during differentiation of Pref-1 null MEF. Prevention of this second increase in ERK1/2 phosphorylation in wild-type MEF by the MEK inhibitor PD98059 or by transient depletion of ERK1/2 via small interfering RNA-enhanced adipocyte differentiation. Furthermore, treatment of Pref-1 null MEF with Pref-1 restores this ERK phosphorylation, resulting in inhibition of adipocyte differentiation primarily by preventing peroxisome proliferator-activated receptor gamma2 induction. However, in the presence of PD98059 or depletion of ERK1/2, exogenous Pref-1 cannot inhibit adipocyte differentiation in Pref-1 null MEF. We conclude that Pref-1 activates MEK/ERK signaling, which is required for Pref-1 inhibition of adipogenesis.
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PMID:Pref-1 (preadipocyte factor 1) activates the MEK/extracellular signal-regulated kinase pathway to inhibit adipocyte differentiation. 1721 Jun 39

We investigated the effect of tigogenin on adipocytic and osteoblastic differentiation in mouse bone marrow stromal cells (BMSCs). Tigogenin enhanced the proliferation of BMSCs significantly. Tigogenin treatment reduced the adipogenic induction of lipid accumulation, visfatin secretion, and the expressions of peroxisome proliferation-activated receptor (PPAR)gamma2 and adipocyte fatty acid-binding protein (ap)2. Moreover, tigogenin had no effect on the mitotic clonal expansion. On the other hand, tigogenin significantly elevated alkaline phosphatase (ALP) activity and the expressions of Cbfa1, collagen type I (COL I) and osteocalcin (OCN), as well as the content of matrix calcium in BMSCs. Further, SB-203580 antagonized the tigogenin-promoted osteogenesis. These observations suggested that tigogenin may modulate differentiation of BMSCs to cause a lineage shift away from the adipocytes and toward the osteoblasts, which is at least mediated by inhibition of PPARgamma and via p38 MAPK pathway, and is a potential drug preventing the development of osteoporosis and the related disorders.
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PMID:Tigogenin inhibits adipocytic differentiation and induces osteoblastic differentiation in mouse bone marrow stromal cells. 1736 41

Rat osteoblasts were cultured for 4 and 5 days aboard a space shuttle and solubilized after a 24-h treatment with 1alpha,25 dihydroxyvitamin D(3). The quantitative RT-PCR determined the mRNA levels of signaling molecules upstream and downstream Ras. The small GTPase is activated by guanine nucleotide exchange protein (GEF) and deactivated by GTPase-activating protein (GAP). When external stimuli are transduced into intracellular signals, various pathways are recruited: focal adhesion kinase (FAK) is associated with integrin-beta, and directs tyrosine phosphorylation of downstream substrates, including phospholipase C-gamma (PLC-gamma) and son of sevenless (SOS, a Ras GEF). The mRNA levels of FAK and PLC-gamma1 and -gamma2 in the flight cultures were increased 150% and 250% of the ground controls. The SOS mRNA levels in the flight cultures were increased 520% and 320% of the ground controls. Signals via G protein-coupled receptors are transmitted through PLC-beta and Ras GRF (another Ras GEF). Activated Ras then stimulates Raf, mitogen-activated protein kinase (MAPK) cascades. The mRNA levels of Raf, extracellular signal-regulated protein kinase of MAPK family (ERK-1 and -2), and PLC-beta were increased during spaceflight. Rho GAP expression in the flight cultures was increased twofold of the ground controls. Since Rho GAP deactivates Rho, microgravity may suppress Rho signals, regulating actin filament rearrangement. Microgravity signals may involve two pathways (G protein-coupled receptor-mediated pathway and tyrosine phosphorylation-mediated pathway) that activate Ras, Raf, and MAPK cascades in rat osteoblasts.
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PMID:Small GTPase Ras and Rho expression in rat osteoblasts during spaceflight. 1740 41

Macrophage colony-stimulating factor (M-CSF) has been found to be involved in multiple developmental processes, especially production of cells belonging to the mononuclear phagocyte system. The decision of myeloid progenitor cells to commit to differentiation depends on activation levels of the mitogen-activated protein kinases (MAPK), ERK1 and ERK2. Using the murine myeloid progenitor cell line FD-Fms, we show here that persistent activity of Src-family kinases (SFK) is necessary for FD-Fms cell differentiation to macrophages in response to M-CSF. Chemical inhibition of SFK blocked FD-Fms cell differentiation while it caused strong inhibition of the late phosphorylation of phospholipase C (PLC)-gamma2 and MAPK. The PLC inhibitor U73122, previously shown to block M-CSF-induced differentiation, strongly decreased long-term MAPK phosphorylation. Interestingly, inhibiting SFK with SU6656 or the MAPK kinases MEK with U0126 significantly impaired development of mononuclear phagocytes in cultures of mouse bone marrow cells stimulated with M-CSF. Collectively, results support a model in which SFK are required for sustained PLC activity and MAPK activation above threshold required for commitment of myeloid progenitors to macrophage differentiation.
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PMID:Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-gamma2 and MAP kinases ERK1 and ERK2. 1797 59


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