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)

A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Thr or Tyr, the majority are extremely sensitive to staurosporine, with IC50 values in the low nanomolar range. A few of them however, notably protein kinases CK1 and CK2, mitogen-activated protein (MAP) kinase and protein-tyrosine kinase CSK, are relatively refractory to staurosporine inhibition, exhibiting IC50 values in the micromolar range. With all protein kinases tested, namely PKA, CK1, CK2, MAP kinase (ERK-1), c-Fgr, Lyn, CSK and TPK-IIB/p38Syk, staurosporine inhibition was competitive with respect to ATP, regardless of its inhibitory power. In contrast, either uncompetitive or noncompetitive kinetics of inhibition with respect to the phosphoacceptor substrate were exhibited by Ser/Thr and Tyr-specific protein kinases, respectively, consistent with a different mechanism of catalysis by these two sub-families of kinases. Computer modeling based on PKA crystal structure in conjunction with sequence analysis suggest that the low sensitivity to staurosporine of CK2 may be accounted for by the bulky nature of three residues, Val66, Phe113 and Ile174 which are homologous to PKA Ala70, Met120 and Thr183, respectively. In contrast these PKA residues are either conserved or replaced by smaller ones in protein kinases highly sensitive to staurosporine inhibition. On the other hand, His160 which is homologous to PKA Glu170, appears to be responsible for the unique behaviour of CK2 with respect to a staurosporine derivative (CGP44171A) bearing a negatively charged benzoyl substituent: while CGP44171A is 10- 100-fold less effective than staurosporine against PKA and most of the other protein kinases tested, it is actually more effective than staurosporine for CK2 inhibition, but it looses part of its efficacy if it is tested on a CK2 mutant (H160D) in which His160 has been replaced by Asp. It can be concluded from these data that the catalytic sites of protein kinases are divergent enough as to allow a competitive inhibitor like staurosporine to be fairly selective, a feature that can be enhanced by suitable modifications designed based on the structure of the catalytic site of the kinase.
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PMID:Different susceptibility of protein kinases to staurosporine inhibition. Kinetic studies and molecular bases for the resistance of protein kinase CK2. 852 58

A growing body of evidence has suggested that oxidative stress causes cardiac injuries during ischemia/reperfusion. Extracellular signal-regulated kinases (ERKs) have been reported to play pivotal roles in many aspects of cell functions and to be activated by oxidative stress in some types of cells. In this study, we examined oxidative stress-evoked signal transduction pathways leading to activation of ERKs in cultured cardiomyocytes of neonatal rats, and determined their role in oxidative stress-induced cardiomyocyte injuries. ERKs were transiently and concentration-dependently activated by hydrogen peroxide (H2O2) in cardiac myocytes. A specific tyrosine kinase inhibitor, genistein, suppressed H2O2-induced ERK activation, while inhibitors of protein kinase A and C or Ca2+ chelators had no effects on the activation. When CSK, a negative regulator of Src family tyrosine kinases, or dominant-negative mutant of Ras or of Raf-1 kinase was overexpressed, activation of transfected ERK2 by H2O2 was abolished. The treatment with H2O2 increased the number of cells stained positive by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and induced formation of DNA ladder and activation of CPP32, suggesting that H2O2 induced apoptosis of cardiac myocytes. When H2O2-induced activation of ERKs was selectively inhibited by PD98059, the number of cardiac myocytes which showed apoptotic death was increased. These results suggest that Src family tyrosine kinases, Ras and Raf-1 are critical for ERK activation by hydroxyl radicals and that activation of ERKs may play an important role in protecting cardiac myocytes from apoptotic death following oxidative stress.
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PMID:Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. 931 82

SHPS-1 is an approximately 120 kDa glycosylated receptor like protein that contains three immunoglobulin-like domains in its extracellular region as well as four potential tyrosine phosphorylation and SRC homology 2 (SH2) domain binding sites in its cytoplasmic region. Lysophosphatidic acid (LPA) stimulated the rapid tyrosine phosphorylation of SHPS-1 and its subsequent association with SHP-2, a protein tyrosine phosphatase containing SH2 domains in Rat-1 fibroblasts. LAP-induced tyrosine phosphorylation of SHPS-1 was inhibited by Clostridium botulinum C3 exoenzyme (which inactivates RHO) but not by pertussis toxin. The protein kinase C activator phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA) also stimulated tyrosine phosphorylation of SHPS-1; however, down-regulation of protein kinase C by prolonged exposure of cells to TPA did not affect LAP-induced tyrosine phosphorylation of SHPS-1. LPA-induced tyrosine phosphorylation of SHPS-1 was markedly reduced in either focal adhesion kinase (FAK)-deficient mouse cells or CHO cells overexpressing the tyrosine kinase CSK. Overexpression of a catalytically inactivate SHP-2 markedly inhibited MAP kinase activation in response to low concentrations of LPA in CHO cells, whereas overexpression of a wild-type SHPS-1 did enhance this effect of LPA. Furthermore, MAP kinase activation in response to a low concentration of LPA was inhibited by botulinum C3 exoenzyme. These results indicate that LPA-induced tyrosine phosphorylation of SHPS-1 and its association with SHP-2 may be mediated by a RHO-dependent pathway that includes FAK and a SRC family kinase. Thus, in addition to its role in receptor tyrosine kinase-mediated MAP kinase activation, the formation of a complex between SHPS-1 and SHP-2 may, in part, play an important role in the activation of MAP kinase in response to low concentrations of LPA.
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PMID:Lysophosphatidic acid-induced association of SHP-2 with SHPS-1: roles of RHO, FAK, and a SRC family kinase. 966 35

The protein tyrosine kinase pp125FAK (focal adhesion kinase, or FAK) is expressed by a variety of cell types and has been implicated in integrin-mediated signaling events. We explored the potential functions of FAK by expressing it de novo in a cell type lacking FAK. We showed previously that cultured human macrophages lack FAK yet still have well-formed focal contacts. Adenovirus-mediated expression of FAK results in the appearance of FAK protein, which localizes to focal contacts and becomes tyrosine-phosphorylated without perturbing overall cell morphology or focal contacts. FAK associates with CSK 48 h after infection and recruits it to focal contacts. Tyrosine phosphorylation of p130cas but not of paxillin is stimulated after FAK expression. The phosphorylation of p130cas is lost at 48 h in parallel with CSK accumulation in focal contacts. The ERK2 form of MAP kinase is similarly activated at 12-24 h, but it also returns to low levels at 48 h. These findings demonstrate that FAK can be reconstituted to focal contacts in cells that lack it without affecting cell morphology or focal contact structure. FAK can regulate the distribution and activities of elements of the MAP kinase signaling pathway.
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PMID:De novo expression of pp125FAK in human macrophages regulates CSK distribution and MAP kinase activation but does not affect focal contact structure. 1004 80

We are interested in identifying, in vascular tissue, nonreceptor tyrosine kinases that may be responsible for the contractile actions of G-protein-coupled agonists such as angiotensin II. By using a series of chromatographic steps, including ion exchange, hydrophobic, and affinity chromatography, we have isolated a major fraction of tyrosine kinase activity from the cytosolic fraction of porcine aorta tissue. According to (i) its immunologic cross-reactivity with the monoclonal anti-cSrc antibody, m327, and with the N-terminally directed monoclonal cSrc2-17 antibody, (ii) its inhibition by the C-terminal cSrc kinase, CSK, and (iii) its specificity for phosphorylating tyrosine 15 in the cdc2(6-20) peptide kinase substrate, we conclude that the kinase we have isolated represents porcine cSrc. A substantial proportion of the enzyme (>70%) was recovered in the cytoplasmic fraction from aorta tissue. The profile of inhibition of the human and porcine cSrc enzymes by a spectrum of tyrosine kinase inhibitors (PP1 >> AG82 > AG490 approximately/= genistein > AG10) was compared with the profile of inhibition of angiotensin II mediated contraction in a porcine coronary vascular preparation (AG10 >> genistein > or = AG82 > or = AG490; PP1 inactive). The different inhibitory profiles indicated that cSrc does not represent the vascular tyrosine kinase responsible for the contractile actions of angiotensin II. We suggest, nonetheless, that cSrc plays a key role for other actions of angiotensin II in intact vascular tissue, such as the regulation of mitogen-activated protein kinase activity and gene transcription.
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PMID:cSrc is a major cytosolic tyrosine kinase in vascular tissue. 1054 24

Epithelial and fibroblast cells were differentially susceptible to transformation by oncogenic src, ras, mos, raf, rac, and cdc42 and the influence of adenovirus E1A. In contrast to NIH 3T3 cells, which are easily transformed by all the oncogenes tested, epithelial cells were more resistant to transformation by the same oncogenes. Transformation efficiency of both primary and immortal epithelial cells by E1B, V12ras, v-src, v-raf, and v-mos was increased by cotransfection of E1A 12S, which enables these cells to overcome the M1/M2 mortality blocks, which are not present in NIH 3T3 cells. NIH 3T3 cell transformation by these oncogenes was not altered by E1A. Although V12cdc42 or V12rac1 alone could produce foci on NIH 3T3 cells, morphological conversion was observed only in the presence of a hypertransforming E1A mutant and not WT E1A. Epithelial cells were not transformed by V12cdc42 or V12rac1, even in the presence of WT or mutant E1A, but could be transformed by coexpression of mos/raf and rac/cdc42, and the resultant phenotype was affected by the E1A C-terminus. Hypertransformation, which has previously been reported with ras and E1A C-terminal mutants, turns out to be due to a synergy with rac/cdc42, but not ERK/MAPK or PI3K ras effectors. Like V12rac, expression of the E1A hypertransforming mutant resulted in the upregulation of vinculin and VASP, concomitant with the altered organization of the actin cytoskeleton in these cells. The results show that in addition to requiring abrogation of M1/M2 mortality blocks, primary epithelial cells require activation of the ERK MAPK cascade and rearrangement of the actin CSK to achieve transformation. In addition, the E1A C-terminus regulates rac/cdc42 function in both epithelial and fibroblast cells to affect the extent of transformation progression.
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PMID:While E1A can facilitate epithelial cell transformation by several dominant oncogenes, the C-terminus seems only to regulate rac and cdc42 function, but in both epithelial and fibroblastic cells. 1075 19

Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal-regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH(2)-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch-induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.
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PMID:Integrins play a critical role in mechanical stress-induced p38 MAPK activation. 1184 90

The lack of good molecular markers for diagnosis as well as treatment assessment has rendered the hepatocellular carcinoma (HCC) a major challenge in health care. In this study, woodchucks were used as an animal model for hepatitis virus-induced HCC, and gene expression studies were performed using a human oligonucleotide microarray. An analysis approach combing supervised significant analysis of microarray (SAM), prediction analysis of microarray (PAM), and unsupervised hierarchical cluster methodologies statistically determined 211 upregulated and 78 downregulated genes between liver cancer and non-cancer liver tissues, and demonstrated > or = 93% accuracy in classifying the tissue samples. RT-PCR results confirmed the differential expression of selected sequenced woodchuck genes (SAT, IDH3B, SCD) in the microarray. Our study showed that differentially expressed genes were involved in transcription, RNA splicing, translation, cell cycle, metabolism, protein folding and degradation, apoptosis, immune response, metal binding, etc. Interestingly, some genes were involved with signaling pathways such as Ras/MAPK (MAPKAP1), Src-dependent pathways (CSK), hedgehog signaling pathway (HHIP), while Wnt signaling pathway may not be dominant in woodchuck HCC as shown by the downregulation of beta-catenin (TNNB1) and the upregulation of CXXC4 and CSNK2B. Numerous genes found in this study were also differentially expressed in human HCC and many other human cancers including breast, prostate and lung cancers, etc., serving as tumor suppressors, promoters, prognostic markers or chemotherapy targets. In conclusion, this study has demonstrated the robustness of the data analysis and the potential of using human microarrays on woodchuck samples. In particular, some of the differentially expressed genes in the woodchuck HCC can be further explored for possible molecular imaging targets or biological markers in human HCC.
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PMID:Gene expression studies of hepatitis virus-induced woodchuck hepatocellular carcinoma in correlation with human results. 1714 10

Toll-like-receptor mediated signaling is finely regulated by a complex intracellular protein network including the interleukin-1 receptor associate kinases (IRAKs). IRAK-4, 1, and 2 may positively regulate innate immunity signaling through the activation of various downstream kinases such as MAPKs. In contrast, IRAK-M plays an inhibitory role through unknown mechanism. In this report, we show that IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. Furthermore, using bone marrow derived macrophages (BMDM) from wild type, IRAK1(-/-), and IRAK-M(-/-) mice, we have herein demonstrated that IRAK-M selectively attenuates bacterial lipopeptide Pam(3)CSK(4)-induced p38 activation, but not ERK or JNK. IRAK1(-/-) and IRAK-M(-/-)BMDM display distinct activation profile of various MAP kinases upon Pam(3)CSK(4) challenge, indicating that IRAK-M exerts its inhibitory effect through an IRAK1 independent pathway. Pam(3)CSK(4) challenge leads to rapid decrease of MKP-1 protein level in IRAK-M(-/-)BMDM as well as THP-1 cells with decreased IRAK-M expression through siRNA interference. Our findings indicate that IRAK-M selectively attenuates p38 activation and inhibits innate immunity through stabilizing MKP-1.
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PMID:Differential regulation and role of interleukin-1 receptor associated kinase-M in innate immunity signaling. 1737 80

The regulation of innate immune responses to pathogens occurs through the interaction of Toll-like receptors (TLRs) with pathogen-associated molecular patterns and the activation of several signaling pathways whose contribution to the overall innate immune response to pathogens is poorly understood. We demonstrate a mechanism of control of murine macrophage responses mediated by TLR1/2 heterodimers through c-Jun N-terminal kinase 1 (JNK1) activity. JNK controls tumor necrosis factor alpha production and TLR-mediated macrophage responses to Borrelia burgdorferi, the causative agent of Lyme disease, and the TLR1/TLR2-specific agonist PAM(3)CSK(4). JNK1, but not JNK2, activity regulates the expression of the tlr1 gene in the macrophage cell line RAW264.7, as well as in primary CD11b(+) cells. We also show that the proximal promoter region of the human tlr1 gene contains an AP-1 binding site that is subjected to regulation by the kinase and binds two complexes that involve the JNK substrates c-Jun, JunD, and ATF-2. These results demonstrate that JNK1 regulates the response to TLR1/2 ligands and suggest a positive feedback loop that may serve to increase the innate immune response to the spirochete.
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PMID:c-Jun N-terminal kinase 1 is required for Toll-like receptor 1 gene expression in macrophages. 1766 70


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