scholarly journals Thyroid hormone stimulation of extracellular signal-regulated kinase and cell proliferation in human osteoblast-like cells is initiated at integrin αVβ3

2008 ◽  
Vol 196 (3) ◽  
pp. 509-517 ◽  
Author(s):  
A Scarlett ◽  
M P Parsons ◽  
P L Hanson ◽  
K K Sidhu ◽  
T P Milligan ◽  
...  
Keyword(s):  
Cell Surface ◽  
Thymidine Incorporation ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cell Surface Receptor ◽  
Human Osteoblast ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Surface Receptor

The aim of the present study was to examine whether triiodo-l-thyronine (T3) or l-thyroxine (T4) rapidly activated the mitogen-activated protein kinase (MAPK) intracellular signalling cascade in osteoblast-like cells and investigate whether this activation was initiated at the integrin αVβ3 cell surface receptor. Using PCR and western blotting, the expression of integrin αVβ3 mRNA and protein was demonstrated in the human osteoblast-like cell lines MG-63 and SaOS-2. The treatment of MG-63 cells with T3 (10 nM) or T4 (100 nM) for 10 min stimulated extracellular signal-regulated kinase activity (ERK, a component of the MAPK pathway) as determined by fluorescent immunocytochemistry and an immunocomplex activity assay (T3 by 10.7-fold, P<0.01 and T4 by 10.4-fold, P<0.01 compared with control). T3 (10 nM) and T4 (100 nM) also significantly stimulated thymidine incorporation into MG-63 cells by 2.3±0.7-fold (P<0.01) and 2.1±0.1-fold (P<0.05) respectively. To establish whether transient ERK activation via the integrin αVβ3 cell surface receptor mediated these effects, MG-63 cells were pretreated for 30 min with the specific MAPK kinase inhibitor, U0126 (1 μM), or an anti-integrin αVβ3-blocking antibody. Both pretreatments significantly inhibited T3- and T4-stimulated ERK activation and abolished T3-stimulated thymidine incorporation (P<0.01). T4-stimulated incorporation was significantly inhibited from 2.1- to 1.3-fold above control (P<0.05). Thus, our results suggest that T3 and T4 rapidly stimulate ERK activation in MG-63 cells via integrin αVβ3 and that one functional effect of this ERK activation is increased DNA synthesis.

scholarly journals A Cdo–Bnip-2–Cdc42 signaling pathway regulates p38α/β MAPK activity and myogenic differentiation

2008 ◽  
Vol 182 (3) ◽  
pp. 497-507 ◽  
Author(s):  
Jong-Sun Kang ◽  
Gyu-Un Bae ◽  
Min-Jeong Yi ◽  
Youn-Joo Yang ◽  
Ji-Eun Oh ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Surface ◽  
Mapk Pathway ◽  
Myogenic Differentiation ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Cell Surface Receptor ◽  
Myoblast Differentiation ◽  
Loss Of Function ◽  
Surface Receptor

The p38α/β mitogen-activated protein kinase (MAPK) pathway promotes skeletal myogenesis, but the mechanisms by which it is activated during this process are unclear. During myoblast differentiation, the promyogenic cell surface receptor Cdo binds to the p38α/β pathway scaffold protein JLP and, via JLP, p38α/β itself. We report that Cdo also interacts with Bnip-2, a protein that binds the small guanosine triphosphatase (GTPase) Cdc42 and a negative regulator of Cdc42, Cdc42 GTPase-activating protein (GAP). Moreover, Bnip-2 and JLP are brought together through mutual interaction with Cdo. Gain- and loss-of-function experiments with myoblasts indicate that the Cdo–Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38α/β activity and cell differentiation. These results reveal a previously unknown linkage between a cell surface receptor and downstream modulation of Cdc42 activity. Furthermore, interaction with multiple scaffold-type proteins is a distinctive mode of cell surface receptor signaling and provides one mechanism for specificity of p38α/β activation during cell differentiation.

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

2007 ◽  
Vol 176 (5) ◽  
pp. 709-718 ◽  
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.

scholarly journals Emerging EPO and EPO receptor regulators and signal transducers

Blood ◽  
2015 ◽  
Vol 125 (23) ◽  
pp. 3536-3541 ◽  
Author(s):  
David Kuhrt ◽  
Don M. Wojchowski
Keyword(s):  
Biological Effects ◽  
Hypoxia Inducible Factor ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Cell Surface Receptor ◽  
Erythroid Progenitors ◽  
Epo Receptor ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Surface Receptor

Abstract As essential mediators of red cell production, erythropoietin (EPO) and its cell surface receptor (EPO receptor [EPOR]) have been intensely studied. Early investigations defined basic mechanisms for hypoxia-inducible factor induction of EPO expression, and within erythroid progenitors EPOR engagement of canonical Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5), rat sarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/MEK/ERK), and phosphatidylinositol 3-kinase (PI3K) pathways. Contemporary genetic, bioinformatic, and proteomic approaches continue to uncover new clinically relevant modulators of EPO and EPOR expression, and EPO’s biological effects. This Spotlight review highlights such factors and their emerging roles during erythropoiesis and anemia.

scholarly journals Posttranslational Regulation of Tristetraprolin Subcellular Localization and Protein Stability by p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Pathways

2006 ◽  
Vol 26 (6) ◽  
pp. 2408-2418 ◽  
Author(s):  
Matthew Brook ◽  
Carmen R. Tchen ◽  
Tomas Santalucia ◽  
Joanne McIlrath ◽  
J. Simon C. Arthur ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Subcellular Localization ◽  
Protein Stability ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
P38 Mapk Pathway ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on MK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.

Delivery of Sorafenib and Metformin Against Hepatocellular Carcinoma with Amphiphilic Polypeptide-based Micelles

2021 ◽  
Author(s):  
Lanqing Cao ◽  
Guangmeng Xu ◽  
Hongyu He ◽  
Jiannan Li
Keyword(s):  
Mapk Pathway ◽  
Synergistic Effects ◽  
Mitogen Activated Protein Kinase ◽  
High Recurrence Rate ◽  
Extracellular Signal Regulated Kinase ◽  
Cycle Arrest ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Poly Ethylene

Abstract Hepatoma is a common clinical disease with poor prognosis and a high recurrence rate. Chemotherapy is important for hepatoma treatment because only a small amount of hepatoma patients are suitable for local resection, and the effects of transarterial chemoembolization (TACE) are unsatisfactory. But many limitations restrict further application of chemotherapy. In this study, sorafenib (Sor) and metformin (Met) co-loaded poly(ethylene glycol)-block-poly(L-glutamic acid-co-L-phenylalanine) (mPEG-b-P(Glu-co-Phe)) micelles were developed. Sor is a common molecular target agent which can inhibit the mitogen-activated protein kinase (MAPK) pathway to treat hepatoma clinically. Met can also regulate the MAPK pathway and inhibit the expression of the phosphorylated extracellular signal-regulated kinase (p-ERK). Moreover, both Sor and Met play important roles in cell cycle arrest. The integration of these two drugs aims to achieve synergistic effects against hepatoma. The micelles can be targeted to cancer cells and possess longer blood circulation time. The two agents can be released rapidly in the tumor sites. Both orthotopic and patient-derived xenograft (PDX) hepatoma models were developed to analyze the treatment efficacy of the Sor and Met loaded micelles. The in vivo study showed that the micelles can prevent hepatoma progression by inhibiting the expressions of p-ERK and cyclin D1. This study indicated that the Sor/Met-loaded micelles are suitable for hepatoma treatment.

The quantity and duration of FcRγ signals determine mast cell degranulation and survival

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3093-3101 ◽  
Author(s):  
Sho Yamasaki ◽  
Eri Ishikawa ◽  
Masayuki Kohno ◽  
Takashi Saito
Keyword(s):  
Mast Cell ◽  
Cell Survival ◽  
Immunoglobulin E ◽  
Mast Cell Degranulation ◽  
Mitogen Activated Protein Kinase ◽  
Cross Linking ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Abstract Immunoglobulin E (IgE) bound to multivalent antigen (Ag) elicits mast cell degranulation but not survival; on the contrary, IgE in the absence of Ag (IgE(-Ag)) induces survival only but not degranulation. Although these distinct responses are mediated through the same receptor, FcϵRI, the molecular mechanism generating the divergence is largely unknown. We recently showed that the signals through FcRγ chain are essential for IgE(-Ag)–induced mast cell survival as well as IgE(+Ag)–induced degranulation. To determine whether the cellular output is regulated by the quantity of FcRγ signal, we expressed CD8/FcRγ chimeras (CD8/γ) in bone marrow–derived mast cells (BMMCs) from FcRγ-/- mice to manipulate the strength of FcRγ signals by anti-CD8 cross-linking. Cross-linking of CD8/γ induced mast cell survival and degranulation. Survival was induced by weaker stimulation than needed for degranulation in terms of anti-CD8 concentration and the valency of chimera. However, sustained extracellular signal-regulated kinase (Erk) activation seems to regulate survival even when the activation signal was strong enough to elicit degranulation. Generation of sustained Erk activation by active mitogen-activated protein kinase kinase (MEK) induced BMMC survival. These results suggest that the duration and the magnitude of FcRγ signals may determine mast cell survival and degranulation, respectively. (Blood. 2004;103:3093-3101)

Temporal Regulation of Light-Induced Extracellular Signal-Regulated Kinase Activation in the Suprachiasmatic Nucleus

2003 ◽  
Vol 90 (6) ◽  
pp. 3854-3863 ◽  
Author(s):  
Greg Q. Butcher ◽  
Boyoung Lee ◽  
Karl Obrietan
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Time Course ◽  
Light Exposure ◽  
Mapk Pathway ◽  
Light Treatment ◽  
Mapk Cascade ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Light Pulses ◽  
Extracellular Signal

Signaling via the p42/p44 mitogen activated protein kinase (MAPK) pathway has been implicated as an intermediate event coupling light to entrainment of the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). To examine how photic input dynamically regulates the activation state of the MAPK pathway, we monitored extracellular signal-regulated kinase (ERK) activation using different light stimulus paradigms. Compared with control animals not exposed to light, a 15 min light exposure during the early night triggered a marked increase in ERK activation and the translocation of ERK from the cytosol to the nucleus. ERK activation peaked 15 min after light onset, then returned to near basal levels within ∼45 min. The MAPK pathway could be reactivated multiple times by light pulses spaced 45 min apart, indicating that the MAPK cascade rapidly resets and resolves individual light pulses into discrete signaling events. Under conditions of constant light (120 min), the time course for ERK activation, nuclear translocation, and inactivation was similar to the time course observed after a 15-min light treatment. The parallels between the ERK inactivation profiles elicited by a 15 and a 120 min light exposure suggest that SCN cells contain a MAPK pathway signal-termination mechanism that limits the duration of pathway activation. This concept was supported by the observation that the small G protein Ras, a regulator of the MAPK pathway, remained in the active, GTP-bound, state under conditions of constant light (120-min duration), indicating that photic information was relayed to the SCN and that SCN cells maintained their responsiveness for the duration of the light treatment. The SCN expressed both nuclear MAPK phosphatases (MKP-1 and MKP-2) and the cytosolic MAPK phosphatase Mkp-3, thus providing mechanisms by which light-induced ERK activation is terminated. Collectively, these observations provide important new information regarding the regulation of the MAPK cascade, a signaling intermediate that couples light to resetting of the SCN clock.

scholarly journals Rac-PAK Signaling Stimulates Extracellular Signal-Regulated Kinase (ERK) Activation by Regulating Formation of MEK1-ERK Complexes

2002 ◽  
Vol 22 (17) ◽  
pp. 6023-6033 ◽  
Author(s):  
Scott T. Eblen ◽  
Jill K. Slack ◽  
Michael J. Weber ◽  
Andrew D. Catling
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Wild Type ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Signaling Complex ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Utilizing mutants of extracellular signal-regulated kinase 2 (ERK2) that are defective for intrinsic mitogen-activated protein kinase or ERK kinase (MEK) binding, we have identified a convergent signaling pathway that facilitates regulated MEK-ERK association and ERK activation. ERK2-Δ19-25 mutants defective in MEK binding could be phosphorylated in response to mitogens; however, signaling from the Raf-MEK pathway alone was insufficient to stimulate their phosphorylation in COS-1 cells. Phosphorylation of ERK2-Δ19-25 but not of wild-type ERK2 in response to Ras V12 was greatly inhibited by dominant-negative Rac. Activated forms of Rac and Cdc42 could enhance the association of wild-type ERK2 with MEK1 but not with MEK2 in serum-starved adherent cells. This effect was p21-activated kinase (PAK) dependent and required the putative PAK phosphorylation sites T292 and S298 of MEK1. In detached cells placed in suspension, ERK2 was complexed with MEK2 but not with MEK1. However, upon replating of cells onto a fibronectin matrix, there was a substantial induction of MEK1-ERK2 association and ERK activation, both of which could be inhibited by dominant-negative PAK1. These data show that Rac facilitates the assembly of a mitogen-activated protein kinase signaling complex required for ERK activation and that this facilitative signaling pathway is active during adhesion to the extracellular matrix. These findings reveal a novel mechanism by which adhesion and growth factor signals are integrated during ERK activation.

scholarly journals Glucocorticoid-Induced Leucine Zipper Inhibits the Raf-Extracellular Signal-Regulated Kinase Pathway by Binding to Raf-1

2002 ◽  
Vol 22 (22) ◽  
pp. 7929-7941 ◽  
Author(s):  
Emira Ayroldi ◽  
Ornella Zollo ◽  
Antonio Macchiarulo ◽  
Barbara Di Marco ◽  
Cristina Marchetti ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Mapk Pathway ◽  
Interleukin 2 ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

ABSTRACT Glucocorticoid-induced leucine zipper (GILZ) is a leucine zipper protein, whose expression is augmented by dexamethasone (DEX) treatment and downregulated by T-cell receptor (TCR) triggering. Stable expression of GILZ in T cells mimics some of the effects of glucocorticoid hormones (GCH) in GCH-mediated immunosuppressive and anti-inflammatory activity. In fact, GILZ overexpression inhibits TCR-activated NF-κB nuclear translocation, interleukin-2 production, FasL upregulation, and the consequent activation-induced apoptosis. We have investigated the molecular mechanism underlying GILZ-mediated regulation of T-cell activation by analyzing the effects of GILZ on the activity of mitogen-activated protein kinase (MAPK) family members, including Raf, MAPK/extracellular signal-regulated kinase (ERK) 1/2 (MEK-1/2), ERK-1/2, and c-Jun NH2-terminal protein kinase (JNK). Our results indicate that GILZ inhibited Raf-1 phosphorylation, which resulted in the suppression of both MEK/ERK-1/2 phosphorylation and AP-1-dependent transcription. We demonstrate that GILZ interacts in vitro and in vivo with endogenous Raf-1 and that Raf-1 coimmunoprecipitated with GILZ in murine thymocytes treated with DEX. Mapping of the binding domains and experiments with GILZ mutants showed that GILZ binds the region of Raf interacting with Ras through the NH2-terminal region. These data suggest that GILZ contributes, through protein-to-protein interaction with Raf-1 and the consequent inhibition of Raf-MEK-ERK activation, to regulating the MAPK pathway and to providing a further mechanism underlying GCH immunosuppression.

scholarly journals The Extracellular Signal-regulated Kinase–Mitogen-activated Protein Kinase Pathway Phosphorylates and Targets Cdc25A for SCFβ-TrCP-dependent Degradation for Cell Cycle Arrest

2009 ◽  
Vol 20 (8) ◽  
pp. 2186-2195 ◽  
Author(s):  
Michitaka Isoda ◽  
Yoshinori Kanemori ◽  
Nobushige Nakajo ◽  
Sanae Uchida ◽  
Katsumi Yamashita ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Genotoxic Stress ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Cycle Arrest ◽  
Erk Phosphorylation ◽  
Extracellular Signal

The extracellular signal-regulated kinase (ERK) pathway is generally mitogenic, but, upon strong activation, it causes cell cycle arrest by a not-yet fully understood mechanism. In response to genotoxic stress, Chk1 hyperphosphorylates Cdc25A, a positive cell cycle regulator, and targets it for Skp1/Cullin1/F-box protein (SCF)β-TrCP ubiquitin ligase-dependent degradation, thereby leading to cell cycle arrest. Here, we show that strong ERK activation can also phosphorylate and target Cdc25A for SCFβ-TrCP-dependent degradation. When strongly activated in Xenopus eggs, the ERK pathway induces prominent phosphorylation and SCFβ-TrCP-dependent degradation of Cdc25A. p90rsk, the kinase downstream of ERK, directly phosphorylates Cdc25A on multiple sites, which, interestingly, overlap with Chk1 phosphorylation sites. Furthermore, ERK itself phosphorylates Cdc25A on multiple sites, a major site of which apparently is phosphorylated by cyclin-dependent kinase (Cdk) in Chk1-induced degradation. p90rsk phosphorylation and ERK phosphorylation contribute, roughly equally and additively, to the degradation of Cdc25A, and such Cdc25A degradation occurs during oocyte maturation in which the endogenous ERK pathway is fully activated. Finally, and importantly, ERK-induced Cdc25A degradation can elicit cell cycle arrest in early embryos. These results suggest that strong ERK activation can target Cdc25A for degradation in a manner similar to, but independent of, Chk1 for cell cycle arrest.

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