scholarly journals Multiple Mitogen-Activated Protein Kinase Signaling Pathways Connect the Cot Oncoprotein to the c-junPromoter and to Cellular Transformation

2000 ◽  
Vol 20 (5) ◽  
pp. 1747-1758 ◽  
Author(s):  
Mario Chiariello ◽  
Maria Julia Marinissen ◽  
J. Silvio Gutkind
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cellular Transformation ◽  
Mitogen Activated Protein Kinase ◽  
Serine Threonine Kinase ◽  
Activated T Cells ◽  
Mapk Kinase ◽  
Threonine Kinase ◽  
Mitogen Activated Protein

ABSTRACT The serine/threonine kinase Cot is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family implicated in cellular transformation. Enhanced expression of this protein has been shown to activate both the MAPK and the c-Jun N-terminal kinase (JNK) pathways and to stimulate the nuclear factor of activated T cells and NF-κB-dependent transcription. However, the nature of the normal functions of the Cot protein and the molecular mechanisms responsible for its oncogenic potential are still largely unknown. Here, we show that overexpression of the cot proto-oncogene is sufficient to stimulate the expression of c-jun and that, in turn, the activity of c-Jun is required for Cot-induced transformation. These observations prompted us to explore the molecular events by which Cot regulates c-jun expression. We found that Cot potently stimulates the activity of the c-jun promoter utilizing JNK-dependent and -independent pathways, the latter involving two novel members of the MAPK family, p38γ (ERK6) and ERK5. Molecularly, this activity was found to be dependent on the ability of Cot to activate, in vivo, members of each class of the MAPK kinase superfamily, including MEK, SEK, MKK6, and MEK5. Furthermore, the use of dominant interfering molecules revealed that Cot requires JNK, p38s, and ERK5 to stimulate the c-jun promoter fully and to induce neoplastic transformation. These findings indicate that Cot represents the first example of a serine/threonine kinase acting simultaneously on all known MAPK cascades. Moreover, these observations strongly suggest that the transforming ability of Cot results from the coordinated activation of these pathways, which ultimately converge on the regulation of the expression and activity of the product of the c-junproto-oncogene.

Mammalian Sterile20-like kinase 1 and the regulation of apoptosis

2004 ◽  
Vol 32 (3) ◽  
pp. 485-488 ◽  
Author(s):  
P.M. de Souza ◽  
M.A. Lindsay
Keyword(s):  
Protein Kinase ◽  
Physiological Function ◽  
Mitogen Activated Protein Kinase ◽  
Serine Threonine Kinase ◽  
Mapk Kinase ◽  
Threonine Kinase ◽  
Abundant Evidence ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

Mammalian Sterile20-like kinase 1 (Mst1) is a ubiquitously expressed serine/threonine kinase which represents a member of the rapidly expanding family of enzymes related to the yeast Sterile20 kinase. Although the physiological function of Mst1 and its role in intracellular signalling is still unclear, reports to date suggest that Mst1, similar to its yeast homologue, operates in the MAPK (mitogen-activated protein kinase) pathway and, in this capacity, may represent a putative MAPK kinase kinase kinase. Moreover, there is abundant evidence for a role of this enzyme in apoptosis, where not only is it a target for caspases, but may also serve as an activator of these proteases to amplify the apoptotic signalling pathway. This paper reviews the investigations that have led to our current understanding of the mechanisms by which Mst1 may be activated and thereby contribute to apoptosis.

scholarly journals Expression and Characterization of the Mycobacterium tuberculosis Serine/Threonine Protein Kinase PknB

1999 ◽  
Vol 67 (11) ◽  
pp. 5676-5682 ◽  
Author(s):  
Yossef Av-Gay ◽  
Sarwat Jamil ◽  
Steven J. Drews
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Infection Model ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Mitogen Activated Protein

ABSTRACT PknB is a member of the newly discovered eukaryotic-like protein serine/threonine kinase (PSTK) family of proteins. The pknBgene was cloned and expressed in Escherichia coli. The active recombinant protein was purified and shown to be reactive with antiphosphoserine antibodies, as well as with antibodies to the phosphorylated eukaryotic Ser/Thr kinases mitogen-activated protein kinase kinase 3 and 6, P38, and Creb. In vitro kinase assays demonstrated that PknB is a functional kinase that is autophosphorylated on serine/threonine residues and is also able to phosphorylate the peptide substrate myelin basic protein. Analysis ofpknB expression in Mycobacterium tuberculosisindicates the presence of pknB mRNA in (i) organisms grown in vitro in bacteriological media, (ii) a murine macrophage in vitro infection model, and (iii) in vivo alveolar macrophages from a patient with tuberculosis.

scholarly journals Raf-1 is a potential substrate for mitogen-activated protein kinase in vivo

1991 ◽  
Vol 277 (2) ◽  
pp. 573-576 ◽  
Author(s):  
N G Anderson ◽  
P Li ◽  
L A Marsden ◽  
N Williams ◽  
T M Roberts ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Mitogen Activated Protein ◽  
Insulin Dependent ◽  
Potential Substrate

MAP (mitogen-activated protein) kinase is shown to phosphorylate baculovirally expressed Raf-1 in vitro, generating one major tryptic phosphopeptide which co-migrated with a peptide from Raf-1 32P-labelled in situ. This peptide also undergoes an insulin-dependent increase in labelling. Thus the serine/threonine kinase Raf-1 may be a substrate for MAP kinase in vivo.

scholarly journals Cell Cycle Arrest and Reversion of Ras-Induced Transformation by a Conditionally Activated Form of Mitogen-Activated Protein Kinase Kinase Kinase 3

1999 ◽  
Vol 19 (5) ◽  
pp. 3857-3868 ◽  
Author(s):  
Heidrun Ellinger-Ziegelbauer ◽  
Kathleen Kelly ◽  
Ulrich Siebenlist
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cyclin D1 ◽  
Stress Responses ◽  
Cell Cycle Progression ◽  
Cellular Transformation ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Progression ◽  
Mapk Kinase ◽  
Mitogen Activated Protein

ABSTRACT Signal-induced proliferation, differentiation, or stress responses of cells depend on mitogen-activated protein kinase (MAPK) cascades, the core modules of which consist of members of three successively acting kinase families (MAPK kinase kinase [MAP3K], MAPK kinase, and MAPK). It is demonstrated here that the MEKK3 kinase inhibits cell proliferation, a biologic response not commonly associated with members of the MAP3K family of kinases. A conditionally activated form of MEKK3 stably expressed in fibroblasts arrests these cells in early G1. MEKK3 critically blocks mitogen-driven expression of cyclin D1, a cyclin which is essential for progression of fibroblasts through G1. The MEKK3-induced block of cyclin D1 expression and of cell cycle progression may be mediated via p38 MAPK, a downstream effector of MEKK3. The MEKK3-mediated block of proliferation also reverses Ras-induced cellular transformation, suggesting possible tumor-suppressing functions for this kinase. Together, these results suggest an involvement of the MEKK3 kinase in negative regulation of cell cycle progression, and they provide the first insights into biologic activities of this kinase.

scholarly journals Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts.

1997 ◽  
Vol 17 (8) ◽  
pp. 4454-4464 ◽  
Author(s):  
Y Tang ◽  
Z Chen ◽  
D Ambrose ◽  
J Liu ◽  
J B Gibbs ◽  
...  
Keyword(s):  
Cellular Transformation ◽  
Mitogen Activated Protein Kinase ◽  
3T3 Cells ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Jun Kinase ◽  
Ras Activation ◽  
Mitogen Activated Protein ◽  
Nih 3T3 ◽  
Dependent Mechanism

Among the mechanisms by which the Ras oncogene induces cellular transformation, Ras activates the mitogen-activated protein kinase (MAPK or ERK) cascade and a related cascade leading to activation of Jun kinase (JNK or SAPK). JNK is additionally regulated by the Ras-related G proteins Rac and Cdc42. Ras also regulates the actin cytoskeleton through an incompletely elucidated Rac-dependent mechanism. A candidate for the physiological effector for both JNK and actin regulation by Rac and Cdc42 is the serine/threonine kinase Pak (p65pak). We show here that expression of a catalytically inactive mutant Pak, Pak1(R299), inhibits Ras transformation of Rat-1 fibroblasts but not of NIH 3T3 cells. Typically, 90 to 95% fewer transformed colonies were observed in cotransfection assays with Rat-1 cells. Pak1(R299) did not inhibit transformation by the Raf oncogene, indicating that inhibition was specific for Ras. Furthermore, Rat-1 cell lines expressing Pak1(R299) were highly resistant to Ras transformation, while cells expressing wild-type Pak1 were efficiently transformed by Ras. Pak1(L83,L86,R299), a mutant that fails to bind either Rac or Cdc42, also inhibited Ras transformation. Rac and Ras activation of JNK was inhibited by Pak1(R299) but not by Pak1(L83,L86,R299). Ras activation of ERK was inhibited by both Pak1(R299) and Pak1(L83,L86,R299), while neither mutant inhibited Raf activation of ERK. These results suggest that Pak1 interacts with components essential for Ras transformation and that inhibition can be uncoupled from JNK but not ERK signaling.

scholarly journals The Molecular Mechanisms of Action of Photobiomodulation Against Neurodegenerative Diseases: A Systematic Review

2020 ◽  
Author(s):  
Mayukha Bathini ◽  
Chandavalli Ramappa Raghushaker ◽  
Krishna Kishore Mahato
Keyword(s):  
Protein Kinase ◽  
Neurodegenerative Diseases ◽  
Cognitive Skills ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Infrared Light ◽  
In Vivo Models ◽  
Therapeutic Benefits ◽  
Mitogen Activated Protein

AbstractNeurodegenerative diseases might be slow but relentless, as we continue to fail in treating or delaying their progression. Given the complexity in the pathogenesis of these diseases, a broad-acting approach like photobiomodulation can prove promising. Photobiomodulation (PBM) uses red and infrared light for therapeutic benefits, working by stimulating growth and proliferation. The implications of photobiomodulation have been studied in several neurodegenerative disease models. It has been shown to improve cell survival, decrease apoptosis, alleviate oxidative stress, suppress inflammation, and rescue mitochondrial function. In in vivo models, it has reportedly preserved motor and cognitive skills. Beyond mitochondrial stimulation, the molecular mechanisms by which photobiomodulation protects against neurodegeneration have not been very well studied. This review has systematically been undertaken to study the effects of photobiomodulation at a molecular level and identify the different biochemical pathways and molecular changes in the process. The data showed the involvement of pathways like extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), and protein kinase B (Akt). In addition, the expression of several genes and proteins playing different roles in the disease mechanisms was found to be influenced by PBM, such as neurotrophic factors and secretases. Studying the literature indicated that PBM can be translated to a potential therapeutic tool, acting through a spectrum of mechanisms that work together to decelerate disease progression in the organism, which is difficult to achieve through pharmacological interventions.

scholarly journals Novel Functions of Death-Associated Protein Kinases through Mitogen-Activated Protein Kinase-Related Signals

2018 ◽  
Vol 19 (10) ◽  
pp. 3031 ◽  
Author(s):  
Mohamed Elbadawy ◽  
Tatsuya Usui ◽  
Hideyuki Yamawaki ◽  
Kazuaki Sasaki
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Family Members ◽  
Mitogen Activated Protein Kinase ◽  
Special Focus ◽  
Main Function ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Death Associated Protein Kinase ◽  
Mitogen Activated Protein

Death associated protein kinase (DAPK) is a calcium/calmodulin-regulated serine/threonine kinase; its main function is to regulate cell death. DAPK family proteins consist of DAPK1, DAPK2, DAPK3, DAPK-related apoptosis-inducing protein kinases (DRAK)-1 and DRAK-2. In this review, we discuss the roles and regulatory mechanisms of DAPK family members and their relevance to diseases. Furthermore, a special focus is given to several reports describing cross-talks between DAPKs and mitogen-activated protein kinases (MAPK) family members in various pathologies. We also discuss small molecule inhibitors of DAPKs and their potential as therapeutic targets against human diseases.

scholarly journals Direct Activation of Mitogen-Activated Protein Kinase Kinase Kinase MEKK1 by the Ste20p Homologue GCK and the Adapter Protein TRAF2

2002 ◽  
Vol 22 (3) ◽  
pp. 737-749 ◽  
Author(s):  
Deborah N. Chadee ◽  
Takashi Yuasa ◽  
John M. Kyriakis
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Mitogen Activated Protein Kinase ◽  
Adapter Protein ◽  
Vitro Assay ◽  
Mapk Kinase ◽  
Surface Receptors ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinase (MAPK) pathways coordinate critical cellular responses to mitogens, stresses, and developmental cues. The coupling of MAPK kinase kinase (MAP3K) → MAPK kinase (MEK) → MAPK core pathways to cell surface receptors remains poorly understood. Recombinant forms of MAP3K MEK kinase 1 (MEKK1) interact in vivo and in vitro with the STE20 protein homologue germinal center kinase (GCK), and both GCK and MEKK1 associate in vivo with the adapter protein tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2). These interactions may couple TNF receptors to the SAPK/JNK family of MAPKs; however, a molecular mechanism by which these proteins might collaborate to recruit the SAPKs/JNKs has remained elusive. Here we show that endogenous GCK and MEKK1 associate in vivo. In addition, we have developed an in vitro assay system with which we demonstrate that purified, active GCK and TRAF2 activate MEKK1. The RING domain of TRAF2 is necessary for optimal in vitro activation of MEKK1, but the kinase domain of GCK is not. Autophosphorylation within the MEKK1 kinase domain activation loop is required for activation. Forced oligomerization also activates MEKK1, and GCK elicits enhanced oligomerization of coexpressed MEKK1 in vivo. These results represent the first activation of MEKK1 in vitro using purified proteins and suggest a mechanism for MEKK1 activation involving induced oligomerization and consequent autophosphorylation mediated by upstream proteins.

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