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)

The stress-activated protein kinases (SAPKs), also known as c-Jun amino-terminal kinases (JNKs), are activated in response to diverse stimuli including DNA damage, heat shock, interleukin-1, tumor necrosis factor-alpha and Fas. Although all these inducers cause apoptosis, whether SAPK/JNK activation is required for apoptosis is controversial. In this study, we demonstrate that ionizing radiation (IR) and dexamethasone (Dex) induce apoptosis in multiple myeloma (MM) derived cell lines, as well as in patient cells. IR-induced apoptosis is associated with activation of SAPK/JNK and p38 kinase, in contrast to Dex-induced apoptosis, which is not associated with activation of stress kinases. Moreover, Dex-induced apoptosis is associated with a significant decrease in the activities of mitogen activated protein kinase (MAPK) and p70S6K, whereas IR-treatment does not alter the activity of these kinases. Both IR and Dex induce poly (ADP ribose) polymerase (PARP) cleavage, a signature event of apoptosis. Finally, interleukin-6 (IL-6) inhibits Dex-induced apoptosis, downregulation of MAP and p70S6K growth kinases and PARP cleavage; in contrast, IL-6 does not inhibit IR-induced apoptosis, activation of SAPK/JNK, and PARP cleavage. Taken together, our findings suggest that SAPK/JNK activation is not required for apoptosis in MM cells, and that there are at least two distinct apoptotic signaling pathways: (i) SAPK/JNK-associated, which is induced by IR and unaffected by IL-6; and (ii) SAPK/JNK-independent, which is induced by Dex, associated with downregulation of MAPK and p70S6K and inhibited by IL-6.
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PMID:Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism. 926 70

The c-Jun N-terminal kinase (JNK), or stress-activated protein kinase plays a crucial role in cellular responses stimulated by environmental stress and proinflammatory cytokines. However, the mechanisms that lead to the activation of the JNK pathway have not been elucidated. We have isolated a cDNA encoding a novel protein kinase that has significant sequence similarities to human germinal center kinase (GCK) and human hematopoietic progenitor kinase 1. The novel GCK-like kinase (GLK) has a nucleotide sequence that encodes an ORF of 885 amino acids with 11 kinase subdomains. Endogenous GLK could be activated by UV radiation and proinflammatory cytokine tumor necrosis factor alpha. When transiently expressed in 293 cells, GLK specifically activated the JNK, but not the p42/44(MAPK)/extracellular signal-regulated kinase or p38 kinase signaling pathways. Interestingly, deletion of amino acids 353-835 in the putative C-terminal regulatory region, or mutation of Lys-35 in the putative ATP-binding domain, markedly reduced the ability of GLK to activate JNK. This result indicates that both kinase activity and the C-terminal region of GLK are required for maximal activation of JNK. Furthermore, GLK-induced JNK activation could be inhibited by a dominant-negative mutant of mitogen-activated protein kinase kinase kinase 1 (MEKK1) or mitogen-activated protein kinase kinase 4/SAPK/ERK kinase 1 (SEK1), suggesting that GLK may function upstream of MEKK1 in the JNK signaling pathway.
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PMID:Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. 927 85

We have identified a new gene, designated lok (lymphocyte-oriented kinase), that encodes a 966-amino acid protein kinase whose catalytic domain at the N terminus shows homology to that of the STE20 family members involved in mitogen-activated protein (MAP) kinase cascades. The non-catalytic domain of LOK does not have any similarity to that of other known members of the family. There is a proline-rich motif with Src homology region 3 binding potential, followed by a long coiled-coil structure at the C terminus. LOK is expressed as a 130-kDa protein, which was detected predominantly in lymphoid organs such as spleen, thymus, and bone marrow, in contrast to other mammalian members of the STE20 family. LOK phosphorylated itself as well as substrates such as myelin basic protein and histone IIA on serine and threonine residues but not on tyrosine residues, establishing LOK as a novel serine/threonine kinase. When coexpressed in COS7 cells with the known MAP kinase isoforms (ERK, JNK, and p38), LOK activated none of them in contrast to PAK- and GCK-related kinases. These results suggest that LOK could be involved in a novel signaling pathway in lymphocytes, which is distinct from the known MAP kinase cascades.
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PMID:LOK is a novel mouse STE20-like protein kinase that is expressed predominantly in lymphocytes. 927 26

Sodium arsenite and osmotic shock both stimulated stress-activated protein kinase-2 (SAPK2, also termed RK, p38, CSBP and Mxi2) and its downstream target mitogen-activated protein kinase (MAP kinase)-activated protein kinase-2 (MAPKAP-K2) in bovine adrenal chromaffin and rat PC12 cells. The same stimuli also increased tyrosine hydroxylase activity 2-3-fold and induced its phosphorylation at Ser19, a residue phosphorylated by MAPKAP-K2 in vitro. The arsenite-induced activation of tyrosine hydroxylase and its phosphorylation at Ser19 were prevented by SB 203580 at concentrations similar to those that inhibited SAPK2 in vitro. These results indicate that MAPKAP-K2 mediates the stress-induced activation of tyrosine hydroxylase. SB 203580 had no effect on the phosphorylation or activation of tyrosine hydroxylase induced by nerve growth factor or forskolin, which trigger the phosphorylation of Ser31 and Ser40, respectively. Stimulation of bovine adrenal chromaffin cells with acetylcholine activated SAPK2 and MAPKAP-K2, as well as p42/p44 MAP kinases and their downstream target MAPKAP-K1. The half-times for activation of MAPKAP-K1 and MAPKAP-K2 (1 min) were similar. In contrast, the activation of tyrosine hydroxylase by acetylcholine peaked within 1 min and gradually declined thereafter. Neither SB 203580 (which blocked the activation of MAPKAP-K2 by acetylcholine) nor PD 98059 (which prevented the activation of p42/p44 MAP kinases by acetylcholine) affected tyrosine hydroxylase activation after 1 min, but these compounds inhibited activation by 40-50% after 5 min. PD 98059 prevented the acetylcholine-induced phosphorylation of tyrosine hydroxylase at Ser31, the residue targetted by p42/p44 MAP kinases in vitro, but did not inhibit the phosphorylation of Ser40 (which is phosphorylated by MAPKAP-K1 in vitro). Our results establish that p42/p44 MAP kinases mediate the acetylcholine-induced phosphorylation of tyrosine hydroxylase at Ser31. SB 203580 did not suppress the phosphorylation of Ser19 or Ser40 by acetylcholine but, like PD 98059, this drug decreased the phosphorylation of Ser31. SAPK2 may therefore contribute to the acetylcholine-induced activation of tyrosine hydroxylase by facilitating (in an unknown way) its phosphorylation by MAP kinases.
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PMID:Participation of a stress-activated protein kinase cascade in the activation of tyrosine hydroxylase in chromaffin cells. 928 46

The p38 mitogen-activated protein kinases (MAPK) are activated by cellular stresses and play an important role in regulating gene expression. We have isolated a cDNA encoding a novel protein kinase that has significant homology (57% amino acid identity) to human p38alpha/CSBP. The novel kinase, p38delta, has a nucleotide sequence encoding a protein of 365 amino acids with a putative TGY dual phosphorylation motif. Dot-blot analysis of p38delta mRNA in 50 human tissues revealed a distribution profile of p38delta that differs from p38alpha. p38delta is highly expressed in salivary gland, pituitary gland, and adrenal gland, whereas p38alpha is highly expressed in placenta, cerebellum, bone marrow, thyroid gland, peripheral leukocytes, liver, and spleen. Like p38alpha, p38delta is activated by cellular stress and proinflammatory cytokines. p38delta phosphorylates ATF-2 and PHAS-I, but not MAPK-activated protein kinase-2 and -3, known in vivo and in vitro substrates of p38alpha. We also observed that p38delta was strongly activated by MKK3 and MKK6, while p38alpha was preferentially activated by MKK6. Other experiments showed that a potent p38alpha kinase inhibitor AMG 2372 minimally inhibited the kinase activity of p38delta. Taken together, these data indicate that p38delta is a new member of the p38 MAPK family and that p38delta likely has functions distinct from that of p38alpha.
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PMID:Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase. 929 8

c-Jun NH2-terminal protein kinase (JNK), a distant member of the mitogen-activated protein (MAP) kinase family, regulates gene expression in response to various extracellular stimuli. JNK is activated by JNK-activating kinase 1 (JNKK1), a dual specificity protein kinase that phosphorylates JNK on threonine 183 and tyrosine 185 residues. Here we show that JNKK2, a novel member of the MAP kinase kinase family, was phosphorylated and activated by MEKK1, a MAP kinase kinase kinase in the JNK signaling cascade. JNKK2 activity was also stimulated by constitutively active forms of Rac and Cdc42Hs, members of the Rho small GTP-binding protein family. Unlike JNKK1 that activates both JNK and p38 MAP kinases, JNKK2 stimulated only JNK. Transient transfection assays demonstrated that JNKK2 potentiated the stimulation of c-Jun transcriptional activity by MEKK1. The existence of multiple JNK-activating kinases may contribute to the specificity of the JNK signaling cascade.
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PMID:Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. 931 68

Three hallmark features of the cardiac hypertrophic growth program are increases in cell size, sarcomeric organization, and the induction of certain cardiac-specific genes. All three features of hypertrophy are induced in cultured myocardial cells by alpha1- adrenergic receptor agonists, such as phenylephrine (PE) and other growth factors that activate mitogen- activated protein kinases (MAPKs). In this study the MAPK family members extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), and p38 were activated by transfecting cultured cardiac myocytes with constructs encoding the appropriate kinases possessing gain-of-function mutations. Transfected cells were then analyzed for changes in cell size, sarcomeric organization, and induction of the genes for the A- and B-type natriuretic peptides (NPs), as well as the alpha-skeletal actin (alpha-SkA) gene. While activation of JNK and/or ERK with MEKK1COOH or Raf-1 BXB, respectively, augmented cell size and effected relatively modest increases in NP and alpha-SkA promoter activities, neither upstream kinase conferred sarcomeric organization. However, transfection with MKK6 (Glu), which specifically activated p38, augmented cell size, induced NP and alpha-Ska promoter activities by up to 130-fold, and elicited sarcomeric organization in a manner similar to PE. Moreover, all three growth features induced by MKK6 (Glu) or PE were blocked with the p38-specific inhibitor, SB 203580. These results demonstrate novel and potentially central roles for MKK6 and p38 in the regulation of myocardial cell hypertrophy.
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PMID:A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. 931 33

Like other members of the tumor necrosis factor (TNF) receptor family, p55 TNF receptor 1 (TNF-R1) lacks intrinsic signaling capacity and transduces signals by recruiting associating molecules. The TNF-R1 associated death domain protein interacts with the p55 TNF-R1 cytoplasmic domain and recruits the Fas-associated death domain protein (which directly activates the apoptotic proteases), the protein kinase receptor interacting protein, and TNF receptor-associated factor 2 (TRAF2). TRAF2 has previously been demonstrated to activate both transcription factor nuclear factor kappaB (NFkappaB) and the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway, which in turn stimulates transcription factor activating protein 1 (AP1) mainly via phosphorylation of the c-Jun component. We have investigated the signaling properties of NFkappaB-inducing kinase (NIK), a TRAF2-associated protein kinase that mediates NFkappaB induction. NIK was found to be unable to activate JNK/SAPK, mitogen-activated protein kinase, or p38 kinase. Moreover, NIK was not required for JNK/SAPK activation by TNF-R1, thus representing the first TNF-R1 complex component to dissect the NFkappaB and the JNK/SAPK pathways. Despite being unable to activate JNK/SAPK and mitogen-activated protein kinase, NIK strongly activated AP1 and was required for TNF-R1-induced AP1 activation. Therefore, NIK links TNF-R1 to a novel, JNK/SAPK-independent, AP1 activation pathway.
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PMID:Tumor necrosis factor (TNF) receptor 1 signaling downstream of TNF receptor-associated factor 2. Nuclear factor kappaB (NFkappaB)-inducing kinase requirement for activation of activating protein 1 and NFkappaB but not of c-Jun N-terminal kinase/stress-activated protein kinase. 933 69

We cloned and characterized a novel human member of the STE20 serine/threonine protein kinase family named mst-3. Based on its domain structure, mst-3 belongs to the SPS1 subgroup of STE20-like proteins, which includes germinal center (GC) kinase, hematopoietic progenitor kinase (HPK), kinase homologous to STE20/SPS-1 (KHS), kinases responsive to stress (KRS1/2), the mammalian STE20-like kinases (mst1/2), and the recently published STE20/oxidant stress response kinase SOK-1. mst-3 is most closely related to SOK-1, with 88% amino acid similarity in the kinase domain. The similarity of the mst-3 kinase domain to STE20 is 42%. The mst-3 transcript is ubiquitously expressed, and the protein was found in all human, mouse, and monkey cell lines tested. An in vitro kinase assay showed that mst-3 can phosphorylate basic exogenous substrates as well as itself. Interestingly, mst-3 prefers Mn2+ to Mg2+ as a divalent cation and can use both GTP and ATP as phosphate donors. Like SOK-1, mst-3 is activated by autophosphorylation. However, a physiological stimulus of mst-3 activity was not identified. mst-3 activity does not change upon exposure to several mitogenic and stress stimuli. Overexpression of mst-3 wild-type or kinase dead protein affects neither the extracellular signal-regulated kinases (ERK1/2 or ERK6), c-Jun N-terminal kinase (JNK), p38, nor pp70S6 kinase, suggesting that mst-3 is part of a novel signaling pathway.
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PMID:Cloning and characterization of a human STE20-like protein kinase with unusual cofactor requirements. 935 38

The high-molecular-mass neurofilament subunit (NFH) is normally hypophosphorylated in the neuronal perikaryon and undergoes extensive phosphorylation after entering the initial axon segment. Aberrant hyperphosphorylation of perikaryal NFH is a common feature of many neurological diseases. In a previous study (), we demonstrated a correlation between phosphorylation of perikaryal NFH and induction of stress-activated protein kinase (SAPK)-gamma. In this report, we present direct evidence showing that the in vivo activation of SAPKs by an upstream activator (MEKK-1) caused extensive NFH phosphorylation. We also show that stress-activated p38 kinases were not involved in the phosphorylation of perikaryal NFH in cultured dorsal root ganglion neurons and that this process was reversible. SAPKgamma was shown to be located in both the cell body and the neurites of the cultured neurons, suggesting that it is likely to be involved in the phosphorylation of cytoplasmic substrates. These could include neuritic NFH, which is highly phosphorylated despite the demonstrated lack of cyclin-dependent kinase-5 activity in these neurons. Neuritic NFH was also highly phosphorylated in neuronal cultures devoid of Schwann cells, indicating that this form of post-translational modification does not require cues stemming from Schwann cell-axon contacts. Collectively, these findings provide significant new insights into mechanisms involved in NFH phosphorylation in normal neurons and in disease states characterized by aberrant phosphorylation of neurofilaments.
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PMID:Study of proline-directed protein kinases involved in phosphorylation of the heavy neurofilament subunit. 939 Oct 2


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