Interactions between extracellular signal‐regulated kinase 1/2 and P38 MAP kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity

Increased prostaglandin production is implicated in the pathogenesis of glomerular disease. With this consideration, we examined the combined effects of reactive oxygen species and platelet-derived growth factor (PDGF), which might initiate glomerular dysfunction, on arachidonic acid release and cytosolic phospholipase A2 (cPLA2) activation in rat mesangial cells. H2O2-induced release of arachidonic acid was enhanced by PDGF, which by itself had little effect on the release, and the enhancement was completely inhibited by a cPLA2 inhibitor. The phosphorylation of cPLA2, extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein (MAP) kinase was upregulated by H2O2 or PDGF alone and except for ERK was enhanced further by the two in combination. The release of arachidonic acid induced by PDGF together with H2O2 was inhibited partially by an inhibitor of ERK or p38 MAP kinase and completely when the two inhibitors were combined; the inhibitory pattern was similar to that for the phosphorylation of cPLA2. These results suggest that the ERK and p38 MAP kinase pathways are involved in the increase in cPLA2activation and arachidonic acid release induced by PDGF together with H2O2.

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Sphingosine kinase 1 is involved in dibutyryl cyclic AMP-induced granulocytic differentiation through the upregulation of extracellular signal-regulated kinase, but not p38 MAP kinase, in HL60 cells

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2004.12.006 ◽

2005 ◽

Vol 1733 (2-3) ◽

pp. 101-110 ◽

Cited By ~ 10

Author(s):

Masahiro Koda ◽

Takashi Murate ◽

Shulin Wang ◽

Kenji Ohguchi ◽

Sayaka Sobue ◽

...

Keyword(s):

Cyclic Amp ◽

Map Kinase ◽

Sphingosine Kinase ◽

P38 Map Kinase ◽

Sphingosine Kinase 1 ◽

Dibutyryl Cyclic Amp ◽

Granulocytic Differentiation ◽

Hl60 Cells ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

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Different pathways leading to activation of extracellular signal-regulated kinase and p38 MAP kinase by formyl-methionyl-leucyl-phenylalanine or platelet activating factor in human neutrophils

Journal of Biomedical Science ◽

10.1007/s11373-005-1704-1 ◽

2005 ◽

Vol 12 (2) ◽

pp. 311-319 ◽

Cited By ~ 23

Author(s):

Lee-Wei Chen ◽

Min-Wai Lin ◽

Ching-Mei Hsu

Keyword(s):

Map Kinase ◽

Platelet Activating Factor ◽

P38 Map Kinase ◽

Human Neutrophils ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

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Iron chelator induces NF-kB activation and interleukin-8 production in human intestinal epithelial cells: Involvement of p38 MAP kinase and extracellular signal-regulated kinase

Gastroenterology ◽

10.1016/s0016-5085(03)81701-8 ◽

2003 ◽

Vol 124 (4) ◽

pp. A337

Author(s):

Eun-Young Choi ◽

Hyun-Mee Oh ◽

Eun-Cheol Kim ◽

Suck-Chei Choi ◽

Young-Woo Soh ◽

...

Keyword(s):

Epithelial Cells ◽

Map Kinase ◽

Intestinal Epithelial Cells ◽

Iron Chelator ◽

P38 Map Kinase ◽

Interleukin 8 ◽

Intestinal Epithelial ◽

Extracellular Signal Regulated Kinase ◽

Human Intestinal Epithelial Cells ◽

Extracellular Signal

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Specific Inactivation and Nuclear Anchoring of Extracellular Signal-Regulated Kinase 2 by the Inducible Dual-Specificity Protein Phosphatase DUSP5

Molecular and Cellular Biology ◽

10.1128/mcb.25.5.1830-1845.2005 ◽

2005 ◽

Vol 25 (5) ◽

pp. 1830-1845 ◽

Cited By ~ 134

Author(s):

Margret Mandl ◽

David N. Slack ◽

Stephen M. Keyse

Keyword(s):

Map Kinase ◽

Mammalian Cells ◽

Map Kinases ◽

Nuclear Translocation ◽

P38 Map Kinase ◽

Nuclear Accumulation ◽

Extracellular Signal Regulated Kinase ◽

Amino Terminal ◽

Extracellular Signal ◽

Map Kinase Phosphatase

ABSTRACT The mechanisms which determine the nuclear accumulation and inactivation of the extracellular signal-regulated kinase 1 (ERK1) or ERK2 mitogen-activated protein (MAP) kinases are poorly understood. Here we demonstrate that DUSP5, an inducible nuclear phosphatase, interacts specifically with ERK2 via a kinase interaction motif (KIM) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of DUSP5 in vivo, as it inactivates ERK2 but not Jun N-terminal protein kinase or p38 MAP kinase. Using green fluorescent protein fusions, we identify within this same domain of DUSP5 a functional nuclear localization signal (NLS) which functions independently of the KIM. Moreover, we demonstrate that the expression of DUSP5 causes both nuclear translocation and sequestration of inactive ERK2. Nuclear anchoring is ERK2 specific and requires both interactions between the DUSP5 KIM and the common docking site of ERK2 and a functional NLS within DUSP5. Finally, the expression of a catalytically inactive mutant of DUSP5 also tethers ERK2 within the nucleus. Furthermore, this nuclear ERK2 is phosphorylated by MAP kinase kinase in response to growth factors and also activates transcription factor Elk-1. We conclude that DUSP5 is an inducible nuclear ERK-specific MAP kinase phosphatase that functions as both an inactivator of and a nuclear anchor for ERK2 in mammalian cells. In addition, our data indicate that the cytoplasm may not be an exclusive site of MAP kinase activation.

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Map kinase signaling pathways and hematologic malignancies

Blood ◽

10.1182/blood-2002-12-3647 ◽

2003 ◽

Vol 101 (12) ◽

pp. 4667-4679 ◽

Cited By ~ 294

Author(s):

Leonidas C. Platanias

Keyword(s):

Map Kinase ◽

Cell Cycle Progression ◽

Map Kinases ◽

Hematologic Malignancies ◽

P38 Map Kinase ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Cellular Context ◽

Regulation Of Cell Cycle ◽

Map Kinase Pathways

AbstractMitogen-activated protein (Map) kinases are widely expressed serine-threonine kinases that mediate important regulatory signals in the cell. Three major groups of Map kinases exist: the p38 Map kinase family, the extracellular signal-regulated kinase (Erk) family, and the c-Jun NH2-terminal kinase (JNK) family. The members of the different Map kinase groups participate in the generation of various cellular responses, including gene transcription, induction of cell death or maintenance of cell survival, malignant transformation, and regulation of cell-cycle progression. Depending on the specific family isoform involved and the cellular context, Map kinase pathways can mediate signals that either promote or suppress the growth of malignant hematopoietic cells. Over the last few years, extensive work by several groups has established that Map kinase pathways play critical roles in the pathogenesis of various hematologic malignancies, providing new molecular targets for future therapeutic approaches. In this review, the involvement of various Map kinase pathways in the pathophysiology of hematologic malignances is summarized and the clinical implications of the recent advances in the field are discussed.

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Glycogen Synthase Kinase 3β and Extracellular Signal-Regulated Kinase Inactivate Heat Shock Transcription Factor 1 by Facilitating the Disappearance of Transcriptionally Active Granules after Heat Shock

Molecular and Cellular Biology ◽

10.1128/mcb.18.11.6624 ◽

1998 ◽

Vol 18 (11) ◽

pp. 6624-6633 ◽

Cited By ~ 118

Author(s):

Bin He ◽

Yong-Hong Meng ◽

Nahid F. Mivechi

Keyword(s):

Transcription Factor ◽

Heat Shock ◽

Transcriptional Activity ◽

Glycogen Synthase ◽

Heat Shock Transcription Factor ◽

Glycogen Synthase Kinase 3Β ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Gsk 3Β ◽

Transcription Factor 1

ABSTRACT Heat shock transcription factor 1 (HSF-1) activates the transcription of heat shock genes in eukaryotes. Under normal physiological growth conditions, HSF-1 is a monomer. Its transcriptional activity is repressed by constitutive phosphorylation. Upon activation, HSF-1 forms trimers, acquires DNA binding activity, increases transcriptional activity, and appears as punctate granules in the nucleus. In this study, using bromouridine incorporation and confocal laser microscopy, we demonstrated that newly synthesized pre-mRNAs colocalize to the HSF-1 punctate granules after heat shock, suggesting that these granules are sites of transcription. We further present evidence that glycogen synthase kinase 3β (GSK-3β) and extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) participate in the down regulation of HSF-1 transcriptional activity. Transient increases in the expression of GSK-3β facilitate the disappearance of HSF-1 punctate granules and reduce hsp-70 transcription after heat shock. We have also shown that ERK is the priming kinase for GSK-3β. Taken together, these results indicate that GSK-3β and ERK MAPK facilitate the inactivation of activated HSF-1 after heat shock by dispersing HSF-1 from the sites of transcription.

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Critical role of the extracellular signal–regulated kinase–MAPK pathway in osteoblast differentiation and skeletal development

The Journal of Cell Biology ◽

10.1083/jcb.200610046 ◽

2007 ◽

Vol 176 (5) ◽

pp. 709-718 ◽

Cited By ~ 337

Author(s):

Chunxi Ge ◽

Guozhi Xiao ◽

Di Jiang ◽

Renny T. Franceschi

Keyword(s):

Transcriptional Activity ◽

Mapk Pathway ◽

Skeletal Development ◽

Critical Role ◽

Dominant Negative ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

The extracellular signal–regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) pathway provides a major link between the cell surface and nucleus to control proliferation and differentiation. However, its in vivo role in skeletal development is unknown. A transgenic approach was used to establish a role for this pathway in bone. MAPK stimulation achieved by selective expression of constitutively active MAPK/ERK1 (MEK-SP) in osteoblasts accelerated in vitro differentiation of calvarial cells, as well as in vivo bone development, whereas dominant-negative MEK1 was inhibitory. The involvement of the RUNX2 transcription factor in this response was established in two ways: (a) RUNX2 phosphorylation and transcriptional activity were elevated in calvarial osteoblasts from TgMek-sp mice and reduced in cells from TgMek-dn mice, and (b) crossing TgMek-sp mice with Runx2+/− animals partially rescued the hypomorphic clavicles and undemineralized calvaria associated with Runx2 haploinsufficiency, whereas TgMek-dn; Runx2+/− mice had a more severe skeletal phenotype. This work establishes an important in vivo function for the ERK–MAPK pathway in bone that involves stimulation of RUNX2 phosphorylation and transcriptional activity.

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