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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has recently been recognized that cellular stresses activate certain members of the mitogen-activated protein kinase (MAPK) superfamily. One role of these "stress-activated" MAPKs is to increase the transactivating activity of the transcription factors c-Jun, Elk1, and ATF2. These findings may be particularly relevant to hearts that have been exposed to pathological stresses. Using the isolated perfused rat heart, we show that global ischemia does not activate the 42- and 44-kD extracellular signal-regulated (protein) kinase (ERK) subfamily of MAPKs but rather stimulates a 38-kD activator of MAPK-activated protein kinase-2 (MAPKAPK2). This activation is maintained during reperfusion. The molecular characteristics of this protein kinase suggest that it is a member of the p38/reactivating kinase (RK) group of stress-activated MAPKs. In contrast, stress-activated MAPKs of the c-Jun N-terminal kinase (JNK/SAPKs) subfamily are not activated by ischemia alone but are activated by reperfusion following ischemia. Furthermore, transfection of ventricular myocytes with activated protein kinases (MEKK1 and SEK1) that may be involved in the upstream activation of JNK/ SAPKs induces increases in myocyte size and transcriptional changes typical of the hypertrophic response. We speculate that activation of multiple parallel MAPK pathways may be important in the responses of hearts to cellular stresses.
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PMID:Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. 875 92

The two-hybrid system for the identification of protein-protein interactions was used to screen for proteins that interact in vivo with the Saccharomyces cerevisiae Pkc1 protein, a homolog of mammalian protein kinase C. Four positive clones were isolated that encoded portions of the protein kinase Mkk1, which acts downstream of Pkc1p in the PKC1-mediated signalling pathway. Subsequently, Pkc1p and the other PKC1 pathway components encoding members of a MAP kinase cascade, Bck1p (a MEKK), Mkk1p, Mkk2p (two functionally homologous MEKs), and Mpk1p (a MAP kinase), were tested pairwise for interaction in the two-hybrid assay. Pkc1p interacted specifically with small N-terminal deletions of Mkk1p, and no interaction between Pkc1p and any of the other known pathway components could be detected. Interaction between Pkc1p and Mkk1p, however, was found to be independent of Mkk1p kinase activity. Bck1p was also found to interact with Mkk1p and Mkk2p, and the interaction required only the predicted C-terminal catalytic domain of Mkk1p. Furthermore, we detected protein-protein interactions between two Bck1p molecules via their N-terminal regions. Finally, Mkk2p and Mpk1p also interacted in the two-hybrid assay. These results suggest that the members of the PKC1-mediated MAP kinase cascade form a complex in vivo and that Pkc1p is capable of directly interacting with at least one component of this pathway.
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PMID:Protein-protein interactions in the yeast PKC1 pathway: Pkc1p interacts with a component of the MAP kinase cascade. 875 99

Because the catalytic domain of dual leucine zipper-bearing kinase (DLK) bears sequence similarity to members of the mitogen-activated protein (MAP) kinase kinase kinase subfamily, this protein kinase was investigated for its ability to activate MAP kinase pathways. When transiently transfected and overexpressed in either COS 7 cells or NIH3T3 cells, wild type DLK potently activated p46(SAPK) (SAPK/JNK) but had no detectable effect in activating p42/44(MAPK). DLK also activated p38(mapk) when overexpressed in NIH3T3 cells. A catalytically inactive point mutant of DLK had no effect in these experiments. Consistent with its specificity in activating SAPK, DLK activated Elk-1 but not Sap1a-mediated transcription. In NIH3T3 cells, activation of SAPK by v-Src was markedly attenuated by coexpression of K185A, a catalytically inactive mutant of DLK, suggesting that this mutant could function in a dominant negative fashion in a pathway that leads from v-Src to SAPKs. In a series of co-transfection experiments, activation of p46(SAPK) by DLK was not inhibited by dominant negative mutants of Rac1 and Cdc42Hs, PAK65-R, or PAK65-A, but was attenuated by MEKK1(K432M). DLK(K185A) did not inhibit the ability of constitutively active MEKK1 to activate SAPK. Moreover, K185A significantly inhibited the activation of SAPK by constitutively active V-12 Rac1 and V-12 Cdc42Hs. These results suggest that DLK lies distal to Rac1 and/or Cdc42Hs but proximal to MEKK1 in a pathway leading from v-Src to SAPKs activation.
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PMID:Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2. 879 50

We previously reported that both hypoxia and hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly and sequentially activate mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1. This was followed by the sequential activation of MAP kinase kinase (MAPKK). MAP kinases (p42mopk and p44mopk), and S6 kinase (p90rsk). In this study, we demonstrated that both hypoxia and hypoxia/ reoxygenation caused rapid activation of Src family tyrosine kinases, p60c-src and p59c-fyn, which are upstream mediators of MAP kinase activation. This was followed by the activation of p21ras. Because Src family tyrosine kinases are known to be cell-surface-associated kinases and upstream regulators of p21ras, these results strongly suggested that activation of Src family tyrosine kinases plays a key role in triggering intracellular signaling cascades in cardiac myocytes in response to hypoxia and hypoxia/reoxygenation.
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PMID:Hypoxia and hypoxia/reoxygenation activate Src family tyrosine kinases and p21ras in cultured rat cardiac myocytes. 880 68

The serine/threonine kinase Raf-1 functions downstream of Rats in a signal transduction cascade which transmits mitogenic stimuli from the plasma membrane to the nucleus. Raf-1 integrates signals coming from extracellular factors and, in turn, activates its substrate, MEK kinase. MEK activates mitogen-activated protein kinase (MAPK), which phosphorylates other kinases as well as transcription factors. Raf-1 exists in a complex with HSP90 and other proteins. The benzoquinone ansamycin geldanamycin (GA) binds to HSP90 and disrupts the Raf-1-HSP90 multimolecular complex, leading to destabilization of Raf-1. In this study, we examined whether Raf-1 destabilization is sufficient to block the Raf-1-MEK-MAPK signalling pathway and whether GA specifically inactivates the Raf-1 component of this pathway. Using the model system of NIH 3T3 cells stimulated with phorbol 12-myristate 13-acetate (PMA), we show that GA does not affect the ability of protein kinase C alpha to be activated by phorbol esters, but it does block activation of MEK and MAPK. Further, GA does not decrease the activity of constitutively active MEK in transiently transfected cells. Finally, disruption of the Raf-1-MEK-MAPK signalling pathway by GA prevents both the PMA-induced proliferative response and PMA-induced activation of a MAPK-sensitive nuclear transcription factor. Thus, we demonstrate that interaction between HSP90 and Raf-1 is a sine qua non for Raf stability and function as a signal transducer and that the effects observed cannot be attributed to a general impairment of protein kinase function.
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PMID:Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. 881 98

Synthesis of the protein kinase Mos is required for progesterone-induced activation of MAP kinase, M-phase promoting factor (MPF), and meiotic maturation of Xenopus oocytes. Mos can function as a MAP kinase kinase kinase, leading to activation of MAP kinase; how Mos causes activation of MPF is not yet known. The protein kinase Raf, which acts as a MAP kinase kinase kinase in somatic cells, also appears to be involved in meiotic maturation, but recent work has suggested that the Raf acts downstream of Mos activity during oocyte maturation. Using an oocyte cell-free system, we report here that a dominant negative Raf, which inhibits Ras-induced MAP kinase activation, does not block Mos-induced activation in vitro. These results indicate that, in contrast to previous conclusions, Mos-induced oocyte MAP kinase activation proceeds independently of Raf. Using a dominant-negative MAP kinase construct, we also show that most of the mitogen-induced hyperphosphorylation and dramatic gel retardation of Raf, which is often taken as a marker for the activation of Raf by upstream components, is actually dependent on, and thus downstream of, MAP kinase activation.
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PMID:Activation of the Xenopus oocyte mitogen-activated protein kinase pathway by Mos is independent of Raf. 882 7

The c-Jun amino-terminal kinases (JNKs)/stress-activated protein kinases (SAPKs) play a crucial role in stress responses in mammalian cells. The mechanism underlying this pathway in the hematopoietic system is unclear, but it is a key in understanding the molecular basis of blood cell differentiation. We have cloned a novel protein kinase, termed hematopoietic progenitor kinase 1 (HPK1), that is expressed predominantly in hematopoietic cells, including early progenitor cells. HPK1 is related distantly to the p21(Cdc42/Rac1)-activated kinase (PAK) and yeast STE20 implicated in the mitogen-activated protein kinase (MAPK) cascade. Expression of HPK1 activates JNK1 specifically, and it elevates strongly AP-1-mediated transcriptional activity in vivo. HPK1 binds and phosphorylates MEKK1 directly, whereas JNK1 activation by HPK1 is inhibited by a dominant-negative MEKK1 or MKK4/SEK mutant. Interestingly, unlike PAK65, HPK1 does not contain the small GTPase Rac1/Cdc42-binding domain and does not bind to either Rac1 or Cdc42, suggesting that HPK1. activation is Rac1/Cdc42-independent. These results indicate that HPK1 is a novel functional activator of the JNK/SAPK signaling pathway.
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PMID:Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. 882 85

Growth factors induce c-fos transcription by stimulating phosphorylation of transcription factor TCF/Elk-1, which binds to the serum response element (SRE). Under such conditions Elk-1 could be phosphorylated by the mitogen-activated protein kinases (MAPKs) ERK1 and ERK2. However, c-fos transcription and SRE activity are also induced by stimuli, such as UV irradiation and activation of the protein kinase MEKK1, that cause only an insignificant increase in ERK1/2 activity. However, both of these stimuli strongly activate two other MAPKs, JNK1 and JNK2, and stimulate Elk-1 transcriptional activity and phosphorylation. We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity. Finally, we show that UV irradiation, but not serum or phorbol esters, stimulate translocation of JNK1 to the nucleus. As Elk-1 is most likely phosphorylated while bound to the c-fos promoter, these results suggest that UV irradiation and MEKK1 activation stimulate TCF/Elk-1 activity through JNK activation, while growth factors induce c-fos through ERK activation.
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PMID:Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. 884 88

Hemodynamic forces play a key role in inducing atherosclerosis-implicated gene expression in vascular endothelial cells. To elucidate the signal transduction pathway leading to such gene expression, we studied the effects of fluid shearing on the activities of upstream signaling molecules. Fluid shearing (shear stress, 12 dynes/cm2 [1 dyne = 10(-5)N]) induced a transient and rapid activation of p21ras and preferentially activated c-Jun NH2 terminal kinases (JNK1 and JNK2) over extracellular signal-regulated kinases (ERK-1 and ERK-2). Cotransfection of RasN17, a dominant negative mutant of Ha-Ras, attenuated the shear-activated JNK and luciferase reporters driven by 12-O-tetradecanoylphorbol-13-acetate-responsive elements. JNK(K-R) and MEKK(K-M), the respective catalytically inactive mutants of JNK1 and MEKK, also partially inhibited the shear-induced luciferase reporters. In contrast, Raf301, ERK(K71R), and ERK(K52R), the dominant negative mutants of Raf-1, ERK-1, and ERK-2, respectively, had little effect on the activities of these reporters. The activation of JNK was also correlated with increased c-Jun transcriptional activity, which was attenuated by a negative mutant of Son of sevenless. Thus, mechanical stimulation exerted by fluid shearing activates primarily the Ras-MEKK-JNK pathway in inducing endothelial gene expression.
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PMID:The Ras-JNK pathway is involved in shear-induced gene expression. 888 24

Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. We report herein the isolation of a cDNA encoding a novel protein kinase designated MAPKKK5 from a human macrophage library. The nucleotide sequence predicts that MAPKKK5 encodes an open reading frame of 1374 amino acids with all 11 kinase subdomains. The putative catalytic domain of MAPKKK5 shows significant sequence homology to the kinase domains of the MAPKKK/MEKK level protein kinases from mouse MEKK2 and -3, Drosophila melanogaster PK92B, Saccharomyces cerevisiae STE11, and Schizosaccharomyces pombe BYR2. Northern blot analysis showed that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. When transiently expressed in COS and 293 cells, MAPKKK5 markedly activated c-Jun N-terminal kinase or stress-activated protein kinase, but not MAPK/ERK. Furthermore, MAPKKK5 that was immunoprecipitated from transfected 293 cells was able to phosphorylate and activate MKK4 in vitro, suggesting that MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway.
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PMID:Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. 894 Jan 79


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