Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Considering that the action of gonadotropin-releasing hormone (GnRH) may be mediated via different signaling pathways in extrapituitary tissues, in the present study we investigated the role of the human GnRH receptor (GnRHR) in activating mitogen-activated protein kinases (MAPKs), which regulate cell growth, division, and differentiation. The phosphorylation state of p44 and p42 MAPKs was examined using antibodies that distinguish phospho-p44/42 MAPK (P-MAPK, Thr(202)/Tyr(204)) from total p44/42 MAPK (T-MAPK, activated plus inactivated) in human ovarian and placental cells. Cell cultures were treated with various concentrations of a GnRH agonist, (D-Ala(6))-GnRH, for 5 min. (D-Ala(6))-GnRH stimulated a rapid activation of P-MAPK in human granulosa-luteal cells (hGLCs) and immortalized extravillous trophoblast (IEVT) cells. Interestingly, (D-Ala(6))-GnRH treatment of ovarian cancer (OVCAR-3) and placental carcinoma (JEG-3) cells induced a biphasic regulatory pattern in P-MAPK activity. In contrast, no change of T-MAPK levels was observed following addition of the GnRH agonist in the ovarian and placental cells examined. The physiological implication of MAPK activation by GnRH in the ovarian and placental cells was also investigated. Human GLCs were treated with (D-Ala(6))-GnRH for 24 h, and progesterone secretion was measured by an established RIA. (D-Ala(6))-GnRH induced a significant decrease in progesterone secretion with maximum inhibition (a 45% decrease over basal level) at 10(-7) M. This inhibitory effect was completely reversed by pretreatment with MAPK/ERK kinase 1 (MEK1) inhibitor (PD98059), suggesting the involvement of the MAPK pathway in hGLCs. Placental JEG-3 cells were treated with (D-Ala(6))-GnRH for 24 h, and betahCG mRNA level was measured using Northern blot analysis. (D-Ala(6))-GnRH stimulated the expression of betahCG mRNA to 160% of control value in JEG-3 cells. In contrast to the ovarian cells, pretreatment of JEG-3 cells with PD98059 failed to block the stimulatory effect of GnRH on betahCG mRNA level, suggesting that other signaling pathway(s) may play a more dominant role in GnRH-induced betahCG mRNA expression. To our knowledge, this is the first demonstration that (1) GnRH induces activation of the MAPK signaling pathway in normal and carcinoma cells of the human ovary and placenta, and (2) MAPK mediates the direct action of GnRH on progesterone production in hGLCs.
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PMID:Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells. 1116 98

Delta opioid receptors (DORs) modulate TCR signaling through the mitogen-activated protein kinases (MAPKs), ERKs 1 and 2. These studies determined whether a DOR agonist alone ([D-Ala(2)-D-Leu(5)]enkephalin; DADLE) affects phosphorylation of the activating transcription factor (ATF-2) and its interaction with the MAPK, c-Jun NH(2)-terminal kinase (JNK). DOR expression was induced on murine splenocytes by anti-CD3 and then quiescent cells were treated with DADLE. DADLE, itself, dose-dependently induced maximal phosphorylation of ATF-2 within 5-10min; naltrindole, a specific antagonist, abolished this. Anti-ATF-2 immunoprecipitates from control and DADLE-treated splenocytes showed a dominant 59kDa phosphorylated band and a 71kDa band. DADLE stimulated phosphorylation of both bands, although the 71kDa band was selectively immunoprecipitated by anti-JNK. Thus, DADLE stimulated phosphorylation of 71kDa ATF-2 and its association with JNK, suggesting that JNK is activated through DORs. Along with previous observations, these studies suggest that lymphocyte DORs can affect the activation of MAPKs by TCR-independent stimulation (e.g., JNK) or indirectly by modulating TCR-dependent stimulation (e.g., ERK).
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PMID:Phosphorylation of activating transcription factor in murine splenocytes through delta opioid receptors. 1274 53

Activation of naive T cells markedly up-regulates the expression of delta opioid receptors (DORs). These receptors are bound by DOR peptides released by T cells, modulating T cell functions such as interleukin-2 production, cellular proliferation, and chemotaxis. Previous studies have shown that DOR agonists [e.g., [D-Ala(2)-D-Leu(5)]-enkephalin (DADLE)] modulate T cell antigen receptor signaling through mitogen-activated protein kinases (MAPKs; i.e., extracellular signal-regulated kinases 1 and 2) and that DORs directly induce phosphorylation of activating transcription factor-2 (implicated in cytokine gene transcription) and its association with the MAPK c-jun1 NH(2)-terminal kinase (JNK). Such observations suggest that DORs may induce the phosphorylation of c-jun. These experiments were performed to test this hypothesis and determine the potential roles of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B). DADLE (10(-10) to 10(-6) M) dose-dependently induced c-jun phosphorylation. This was blocked by pertussis toxin and the DOR-specific antagonist naltindole. Fluorescence flow cytometry showed that DADLE significantly stimulated c-jun phosphorylation by T cells. DADLE stimulated phosphorylation of membrane-associated Akt; wortmannin and LY294002 ([2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one]), specific inhibitors of PI3K, abolished the DADLE-induced phosphorylation of c-jun. Finally, inhibitors of Akt and JNK blocked DADLE-induced phosphorylation of c-jun. Thus, activated DORs directly stimulate c-jun phosphorylation through a PI3K-dependent pathway in T cells, apparently involving Akt. This implies that DORs activate JNK through a novel pathway dependent on PI3K and Akt, thereby regulating the function of activator protein-1 transcription complexes containing c-jun and other transcription partners.
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PMID:delta opioid receptors stimulate Akt-dependent phosphorylation of c-jun in T cells. 1624 73

It is well known that angiotensin-(1-7) (Ang-(1-7)) counterbalances vasoconstrictive and proliferative functions of angiotensin II (Ang II), some of those actions are via inhibition of Ang II induced activation of mitogen-activated protein kinases(MAPK). This study investigated the effects of Ang-(1-7) on Ang II-mediated cell signaling pathways in mouse bone marrow-derived dendritic cells (DC). The expression of receptor Mas and angiotensin-converting enzyme-related carboxypeptidase (ACE2) mRNA was examined by reverse transcription-polymerase chain reaction (RT-PCR); activation of MAPK was detected by immunoblotting after incubation of dendritic cells with Ang II in the presence or absence of Ang-(1-7), valsartan, PD123319, and D-Ala(7)-Ang-(1-7). Ang II rapidly (5 min, 10(-7) mol/L) stimulated phosphorylation of extracellular signal-related kinase (ERK1/2); this effect was partially inhibited by Ang II type 1 (AT1) receptor antagonist valsartan and significantly attenuated by Ang II type 2 (AT2) receptor antagonist PD123319. Ang-(1-7) alone also induced phosphorylation of ERK1/2; co-treatment of Ang-(1-7) and Ang II markedly enhanced ERK1/2 phosphorylation, the enhancement was eliminated by the Ang-(1-7) receptor antagonist D-Ala(7)-Ang-(1-7). Both Ang-(1-7) and Ang II had no effect on p38 and c-Jun N-terminal kinase (JNK) phosphorylation. In conclusion, Ang II stimulates ERK1/2 phosphorylation via AT2 receptor in mouse DC, Ang-(1-7) enhances this effect. Generation of Ang-(1-7) by DC could thereby counteract on the pro-inflammatory function of locally generated Ang II.
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PMID:Angiotensin-(1-7) enhances angiotensin II induced phosphorylation of ERK1/2 in mouse bone marrow-derived dendritic cells. 1904 Nov 35