Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that activation of nicotinic acetylcholine receptors (nAChRs) enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of alpha7 nAChR. In the present studies, mechanisms underlying the acute and chronic nicotinic enhancement of LTP were examined. In particular, the involvement of activation of intracellular kinases was examined using selective kinase antagonists, and the effects of enhancing cholinergic function with positive allosteric modulators of the alpha7 nAChR and with acetylcholinesterase (AChE) inhibitors were also investigated. Activation of extracellular signal-regulated kinase (ERK) and cAMP-dependent protein kinase (PKA) was found to be involved in the induction of the acute nicotinic enhancement of LTP, although not control LTP. In contrast, activation of the tyrosine kinase Src, Ca(2+)-calmodulin-dependent protein kinase II, Janus kinase 2 and p38 mitogen-activated protein kinase was not involved in the acute nicotinic enhancement of LTP, although Src activation was necessary for control LTP. Moreover, activation of phosphoinositide 3-kinase was involved in the acute nicotinic enhancement of LTP to a much lesser extent than in control LTP. Chronic nicotine enhancement of LTP was found to be dependent on PKA, ERK and Src kinases. Acute nicotinic enhancement of LTP was occluded by chronic nicotine treatment. The positive allosteric modulator PNU-120596 was found to strongly reduce the threshold for nicotinic enhancement of LTP, an affect mediated via the alpha7 nAChR as it was blocked by the selective antagonist methyllycaconitine. The AChE inhibitors tacrine and physostigmine enhanced control LTP.
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PMID:Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus. 1907 24

Here we demonstrated that the 'loss of function' of not-rearranged c-ABL in chronic myeloid leukemia (CML) is promoted by its cytoplasmic compartmentalization bound to 14-3-3 sigma scaffolding protein. In particular, constitutive tyrosine kinase (TK) activity of p210 BCR-ABL blocks c-Jun N-terminal kinase (JNK) phosphorylation leading to 14-3-3 sigma phosphorylation at a critical residue (Ser(186)) for c-ABL binding in response to DNA damage. Moreover, it is associated with 14-3-3 sigma over-expression arising from epigenetic mechanisms (promoter hyper-acetylation). Accordingly, p210 BCR-ABL TK inhibition by the TK inhibitor Imatinib mesylate (IM) evokes multiple events, including JNK phosphorylation at Thr(183), p38 mitogen-activated protein kinase (MAPK) phosphorylation at Thr(180), c-ABL de-phosphorylation at Ser residues involved in 14-3-3 binding and reduction of 14-3-3 sigma expression, that let c-ABL release from 14-3-3 sigma and nuclear import, and address BCR-ABL-expressing cells towards apoptotic death. Informational spectrum method (ISM), a virtual spectroscopy method for analysis of protein interactions based on their structure, and mathematical filtering in cross spectrum (CS) analysis identified 14-3-3 sigma/c-ABL binding sites. Further investigation on CS profiles of c-ABL- and p210 BCR-ABL-containing complexes revealed the mechanism likely involved 14-3-3 precluded phosphorylation in CML cells.
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PMID:14-3-3 ligand prevents nuclear import of c-ABL protein in chronic myeloid leukemia. 1922 Aug 9

Bcr-abl signals for leukemogenesis of chronic myeloid leukemia (CML) and activates ras. Since the function of promyelocytic leukemia protein (pml) is provoked by ras to promote apoptosis and senescence in untransformed cells, the function is probably masked in CML. Imatinib specifically inhibits bcr-abl and induces apoptosis of CML cells. As reported previously, p53(wild) CML was more resistant to imatinib than that lacking p53. Here, we searched for an imatinib-induced p53 independent proapoptotic mechanism. We found imatinib up-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73; expression of pml and bax; formation of PML-nuclear body (NB); and co-localization of TAp73/PML-NB in p53-nonfunctioning K562 and p53(mutant) Meg-01 CML cells, but not in BCR-ABL(-) HL60 cells. In K562 cells, with short interfering RNAs (siRNAs), knockdown of pml led to dephosphorylation of TAp73. Knockdown of either pml or TAp73 abolished the imatinib-induced apoptosis. Inhibition of p38 MAPK with SB203580 led to dephosphorylation of TAp73, abolishment of TAp73/PML-NB co-localization, and the subsequent apoptosis. Conversely, interferon alpha-2a (IFNalpha), which increased phosphrylated TAp73 and TAp73/PML-NB co-localization, increased additively apoptosis with imatinib. The imatinib-induced TAp73/PML-NB co-localization was accompanied by co-immpunoprecipitation of TAp73 with pml. The imatinib-induced co-localization was also found in primary CML cells from 3 of 6 patients, including 2 with p53(mutant) and one with p53(wild). A novel p53-independent proapoptotic mechanism using p38 MAPK /pml/TAp73 axis with a step processing at PML-NB and probably with chk2 and bax being involved is hereby evident in some imatinib-treated CML cells.
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PMID:Pml and TAp73 interacting at nuclear body mediate imatinib-induced p53-independent apoptosis of chronic myeloid leukemia cells. 1929 93

Osteopontin plays a pivotal role in the progression of interstitial fibrosis in renal ischemia. In the present study, rat renal tubular NRK52E cells treated with hypoxia mimetic cobalt chloride (CoCl(2)) increased osteopontin production, and are associated with increased phosphorylation of Akt/PKB (protein kinase B) and p38 mitogen-activated protein kinase (p38MAPK). Furthermore, pretreatment of cells with l-N-acetylcysteine (an antioxidant) inhibited CoCl(2)-stimulated osteopontin protein expression and p38MAPK phosphorylation, but not Akt/PKB phosphorylation. Pretreatment of cells with anti-inflammatory agents celecoxib, tanshinone IIA, and dipyridamole inhibited CoCl(2)-induced osteopontin production paralleled by heme oxygenase-1 (HO-1) induction. Pretreatment of cells with tin protoporphyrin (a HO-1 inhibitor) or hemoglobin (a carbon monoxide scavenging agent) reversed dipyridamole inhibition of osteopontin expression. Moreover, transfection of HO-1 small interfering RNA (siRNA) reduced dipyridamole-stimulated mitogen-activated protein kinase phosphatase-1 (MKP-1) phosphorylation. Conversely, MKP-1 knockdown reversed dipyridamole inhibition of osteopontin expression. Taken together, these data suggest that dipyridamole may inhibit CoCl(2)-induced osteopontin expression through HO-1 induction. Increased HO-1 may catalyze the conversion of heme into carbon monoxide, in turn carbon monoxide activates MKP-1. MKP-1 activation inhibits the p38MAPK signaling pathway that mediates CoCl(2)-induced osteopontin production.
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PMID:Dipyridamole inhibits cobalt chloride-induced osteopontin expression in NRK52E cells. 1935 21

Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-kappaB in primary hepatocytes and pharmacological inhibition of NF-kappaB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with "STAT3 Inhibitor VI," however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-kappaB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.
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PMID:Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. 1960 29

Expression and activity of the germinal center kinase [corrected] SLK are increased during kidney development and recovery from renal ischemia-reperfusion injury. SLK promotes apoptosis, in part, via pathway(s) involving apoptosis signal-regulating kinase-1 and p38 mitogen-activated protein kinase. This study addresses the role of p53 as a potential effector of SLK. p53 transactivation was measured after transient transfection of a luciferase reporter plasmid that contains a p53 cis-acting enhancer element. Overexpression of SLK in COS-1 cells and cotransfection of SLK and p53-wild type (wt) cDNAs in glomerular epithelial cells (GECs) stimulated p53 transactivational activity, as measured by a p53 response element-driven luciferase reporter. In GECs, chemical anoxia followed by glucose reexposure (in vitro ischemia-reperfusion) increased p53 reporter activity, and this increase was amplified by overexpression of SLK. Expression of SLK induced p53 phosphorylation on serine (S)-33 and S315. In GECs, cotransfection of SLK with p53-wt, p53-S33A, p53-S315A, or p53-S33A+S315A mutants showed that only the double mutation abolished the SLK-induced increase in p53 reporter activity. SLK-induced stimulation of p53 reporter activity was attenuated by inhibition of JNK. Overexpression of SLK amplified apoptosis induced by subjecting cells to in vitro ischemia-reperfusion injury, while ectopic expression of a dominant negative SLK mutant attenuated the ischemia-reperfusion-induced apoptosis. The p53 transactivation inhibitor pifithrin-alpha significantly attenuated the amount of apoptosis after ischemia-reperfusion and SLK overexpression. Thus SLK induces p53 phosphorylation and transactivation, which enhances apoptosis after in vitro ischemia-reperfusion injury.
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PMID:The Ste20-like kinase SLK promotes p53 transactivation and apoptosis. 1964 Aug 99

The adaptor protein Crk mediates intracellular signaling related to cell motility and proliferation and is implicated in human tumorigenesis. The role of Crk in the growth of human sarcoma has remained unclear, however. The present study shows that Crk-induced activation of Src and subsequent signaling by p38 mitogen-activated protein kinase (MAPK) contribute to the enhanced proliferation of human synovial sarcoma cells. Depletion of Crk by RNA interference markedly inhibited proliferation of the synovial sarcoma cell lines HS-SYII, SYO-1, and Fuji as well as prevented anchorage-independent growth. Conversely, reconstitution with CrkII by authentic small interfering RNA-resistant Crk gene restored proliferation in Crk-silenced SYO-1 cells. Crk-depleted synovial sarcoma cells manifested enhanced transcriptional activity and expression of the p16(INK4A) gene, resulting in their accumulation in G(1) phase of the cell cycle. In response to hepatocyte growth factor stimulation, Crk prominently induced the tyrosine phosphorylation of Grb2-associated binder 1 through activation of Src and focal adhesion kinase, and the Src family kinase inhibitor PP2 almost completely inhibited the proliferation of SYO-1 cells. Crk also induced the phosphorylation of p38 MAPK, and SB203580, a p38 MAPK-specific inhibitor, increased expression of p16(INK4A) gene in SYO-1 cells. Furthermore, SB203580 or depletion of p38 MAPK by small interfering RNA suppressed both the phosphorylation of Akt triggered by hepatocyte growth factor and the proliferation of SYO-1 cells. These results suggest that Crk promotes proliferation of human synovial sarcoma cells through activation of Src and its downstream signaling by a novel p38 MAPK-Akt pathway, with these signaling molecules providing potent new targets for molecular therapeutics.
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PMID:Adaptor protein Crk induces Src-dependent activation of p38 MAPK in regulation of synovial sarcoma cell proliferation. 1973 74

Shockwaves elicited by transient pressure disturbances are used to treat musculoskeletal disorders. Previous research has shown that shockwave treatment affects T-cell function, enhancing T-cell proliferation and IL-2 expression by activating p38 mitogen-activated protein kinase (MAPK) signaling. Here we investigated the signaling pathway by which shockwaves mediate p38 MAPK phosphorylation. We found that shockwaves at an intensity of 0.18 mJ/mm(2) induce the release of extracellular ATP from human Jurkat T-cells at least in part by affecting cell viability. ATP released into the extracellular space stimulates P2X7-type purinergic receptors that induce the activation of p38 MAPK and of focal adhesion kinase (FAK) by phosphorylation on residues Tyr397 and Tyr576/577. Elimination of released ATP with apyrase or inhibition of P2X7 receptors with the antagonists KN-62 or suramin significantly weakens FAK phosphorylation, p38 MAPK activation, IL-2 expression, and T-cell proliferation. Conversely, addition of exogenous ATP causes phosphorylation of FAK and p38 MAPK. Silencing of FAK expression also reduces these cell responses to shockwave treatment. We conclude that shockwaves enhance p38 MAPK activation, IL-2 expression, and T-cell proliferation via the release of cellular ATP and feedback mechanisms that involve P2X7 receptor activation and FAK phosphorylation.
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PMID:Shockwaves increase T-cell proliferation and IL-2 expression through ATP release, P2X7 receptors, and FAK activation. 2007 88

3,5,3',4',5'-pentamethoxystilbene (MR-5) is a synthetically methoxylated analogue of resveratrol and has been suggested to have antitumor activity because of structural similarity to resveratrol. Herein, we investigate the antiproliferative effect of MR-5 in human breast cancer MCF-7 cells and demonstrate that MR-5 had a more potent inhibition on cell growth compared with resveratrol and other methoxylated derivatives. Exploring the growth-inhibitory mechanisms of MR-5, we found that it is accompanied by G1 cell cycle arrest, which coincides with a marked inhibition of G1 cell cycle regulatory proteins, including decreased cyclins (D1/D3/E) and cyclin-dependent kinases (CDK2/4/6) and increased CDK inhibitors (CKIs) such as p15, p16, p21, and p27. Furthermore, the increase in CKI levels by MR-5 resulted in a concomitant increase in their interactions of CDK4 and CDK2, along with a strong inhibition in CDK4 kinase activity and the accumulation of hypophosphorylated Rb. MR-5 also modulated some critical kinase activities related to cell cycle regulation, including Akt, mitogen-activated protein kinase (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), and focal adhesion kinase (FAK) in MCF-7 cells. In total, our results demonstrate that MR-5 affects multiple cellular targets that contribute to its antiproliferative activity in MCF-7 cells and provide novel information for synthetic chemists to design new antitumor agents with introduction of methoxylated group(s) in the basic compound.
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PMID:3,5,3',4',5'-pentamethoxystilbene (MR-5), a synthetically methoxylated analogue of resveratrol, inhibits growth and induces G1 cell cycle arrest of human breast carcinoma MCF-7 cells. 1991 42

Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. To explore whether cinnamaldehyde was linked to altered high glucose (HG)-mediated renal tubulointerstitial fibrosis in diabetic nephropathy (DN), the molecular mechanisms of cinnamaldehyde responsible for inhibition of HG-induced hypertrophy in renal interstitial fibroblasts were examined. We found that cinnamaldehyde caused inhibition of HG-induced cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, cleaved poly(ADP-ribose) polymerase (PARP) protein expression, and mitochondrial cytochrome c release in HG or cinnamaldehyde treatments in these cells. HG-induced extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) (but not the Janus kinase 2/signal transducers and activators of transcription) activation was markedly blocked by cinnamaldehyde. The ability of cinnamaldehyde to inhibit HG-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of collagen IV, fibronectin, and alpha-smooth muscle actin (alpha-SMA). The results obtained in this study suggest that cinnamaldehyde treatment of renal interstitial fibroblasts that have been stimulated by HG reduces their ability to proliferate and hypertrophy through mechanisms that may be dependent on inactivation of the ERK/JNK/p38 MAPK pathway.
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PMID:Cinnamaldehyde impairs high glucose-induced hypertrophy in renal interstitial fibroblasts. 2006 12


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