scholarly journals Downregulation of the Ras–Mitogen-Activated Protein Kinase Pathway by the EphB2 Receptor Tyrosine Kinase Is Required for Ephrin-Induced Neurite Retraction

2001 ◽  
Vol 21 (21) ◽  
pp. 7429-7441 ◽  
Author(s):  
Sabine Elowe ◽  
Sacha J. Holland ◽  
Sarang Kulkarni ◽  
Tony Pawson
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Mapk Pathway ◽  
Neuronal Cells ◽  
Mitogen Activated Protein Kinase ◽  
Neurite Retraction ◽  
Mitogen Activated Protein ◽  
Stimulation Of

ABSTRACT Activation of the EphB2 receptor tyrosine kinase by clustered ephrin-B1 induces growth cone collapse and neurite retraction in differentiated NG108 neuronal cells. We have investigated the cytoplasmic signaling events associated with EphB2-induced cytoskeletal reorganization in these neuronal cells. We find that unlike other receptor tyrosine kinases, EphB2 induces a pronounced downregulation of GTP-bound Ras and consequently of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. A similar inhibition of the Ras-MAPK pathway was observed on stimulation of endogenous EphB2 in COS-1 cells. Inactivation of Ras, induced by ephrin B1 stimulation of NG108 neuronal cells, requires EphB2 tyrosine kinase activity and is blocked by a truncated form of p120-Ras GTPase-activating protein (p120-RasGAP), suggesting that EphB2 signals through the SH2 domain protein p120-RasGAP to inhibit the Ras-MAPK pathway. Suppression of Ras activity appears functionally important, since expression of a constitutively active variant of Ras impaired the ability of EphB2 to induce neurite retraction. In addition, EphB2 attenuated the elevation in ERK activation induced by attachment of NG108 cells to fibronectin, indicating that the EphB2 receptor can modulate integrin signaling to the Ras GTPase. These results suggest that a primary function of EphB2, a member of the most populous family of receptor tyrosine kinases, is to inactivate the Ras-MAPK pathway in a fashion that contributes to cytoskeletal reorganization and adhesion responses in neuronal growth cones.

Role of tyrosine kinase and p44/42 MAPK in D2-like receptor-mediated stimulation of Na+, K+-ATPase in kidney

2002 ◽  
Vol 282 (4) ◽  
pp. F697-F702 ◽  
Author(s):  
Vihang Narkar ◽  
Tahir Hussain ◽  
Mustafa Lokhandwala
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Rat Kidney ◽  
Receptor Activation ◽  
Proximal Tubules ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Stimulation Of

Our laboratory has shown that dopamine D2-like receptor activation causes stimulation of Na+, K+-ATPase (NKA) activity in the proximal tubules of the rat kidney. The present study was designed to investigate the cellular signaling mechanisms mediating this response to D2-like receptor activation. We measured the stimulation of NKA activity by bromocriptine (D2-like receptor agonist) in the absence and presence of PD-98059 [p44/42 mitogen-activated protein kinase (MAPK) kinase inhibitor] and genistein (tyrosine kinase inhibitor) in renal proximal tubules. Both agents inhibited bromocriptine-mediated stimulation of NKA, suggesting the involvement of p44/42 MAPK and tyrosine kinase in this response. Additionally, we found that bromocriptine increased the phosphorylation of p44/42 MAPK in the proximal tubules, which was blocked by PD-98059 and genistein. These results show that D2-like receptor activation causes stimulation of NKA activity by means of a tyrosine kinase-p44/42 MAPK pathway in the proximal tubules of the kidney.

scholarly journals Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation

2001 ◽  
Vol 154 (2) ◽  
pp. 345-354 ◽  
Author(s):  
Jan Grimm ◽  
Martin Sachs ◽  
Stefan Britsch ◽  
Silvana Di Cesare ◽  
Thomas Schwarz-Romond ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Neuronal Differentiation ◽  
Pc12 Cells ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Family Members ◽  
Mitogen Activated Protein Kinase ◽  
New Family ◽  
Neuronal Tissues ◽  
Mitogen Activated Protein

Docking proteins are substrates of tyrosine kinases and function in the recruitment and assembly of specific signal transduction molecules. Here we found that p62dok family members act as substrates for the c-Ret receptor tyrosine kinase. In addition to dok-1, dok-2, and dok-3, we identified two new family members, dok-4 and dok-5, that can directly associate with Y1062 of c-Ret. Dok-4 and dok-5 constitute a subgroup of dok family members that is coexpressed with c-Ret in various neuronal tissues. Activated c-Ret promotes neurite outgrowth of PC12 cells; for this activity, Y1062 in c-Ret is essential. c-Ret/dok fusion proteins, in which Y1062 of c-Ret is deleted and replaced by the sequences of dok-4 or dok-5, induce ligand-dependent axonal outgrowth of PC12 cells, whereas a c-Ret fusion containing dok-2 sequences does not elicit this response. Dok-4 and dok-5 do not associate with rasGAP or Nck, in contrast to p62dok and dok-2. Moreover, dok-4 and dok-5 enhance c-Ret–dependent activation of mitogen-activated protein kinase. Thus, we have identified a subclass of p62dok proteins that are putative links with downstream effectors of c-Ret in neuronal differentiation.

Signaling in new directions

1995 ◽  
Vol 73 (3-4) ◽  
pp. 133-136 ◽  
Author(s):  
Haleh Vahidi Samiei
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Molecular Level ◽  
Clear Cut ◽  
New Directions

Many laboratories, using a variety of organisms, have contributed to deciphering the identity and the order of the components leading from ligand-bound receptor tyrosine kinases to various intracellular events, including changes in gene expression. The gaps have only been filled recently. This minireview summarizes the findings and points out the degree of conservation of the same pathway in distant organisms, both at the molecular level and in terms of the consecutive steps. The review also looks at points at which this pathway might be diverging and points onto which other pathways might be converging. These interactions are not always clear cut, and understanding them will be the challenge for the future.Key words: signal transduction, receptor tyrosine kinase, RAS, RAF, MAP kinase.

scholarly journals Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 513 ◽  
Author(s):  
Marina Leite ◽  
Miguel S. Marques ◽  
Joana Melo ◽  
Marta T. Pinto ◽  
Bruno Cavadas ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Receptor Activation ◽  
Degradation Pathway ◽  
Mrna Levels ◽  
H Pylori

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.

scholarly journals The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is required for virus multiplication

2004 ◽  
Vol 381 (2) ◽  
pp. 437-446 ◽  
Author(s):  
Anderson A. ANDRADE ◽  
Patrícia N. G. SILVA ◽  
Anna C. T. C. PEREIRA ◽  
Lirlândia P. de SOUSA ◽  
Paulo C. P. FERREIRA ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Vaccinia Virus ◽  
Mapk Pathway ◽  
Decisive Role ◽  
Virus Multiplication ◽  
Mitogen Activated Protein Kinase ◽  
Actin Dynamics ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Early events play a decisive role in virus multiplication. We have shown previously that activation of MAPK/ERK1/2 (mitogen-activated protein kinase/extracellular-signal-regulated kinase 1/2) and protein kinase A are pivotal for vaccinia virus (VV) multiplication [de Magalhães, Andrade, Silva, Sousa, Ropert, Ferreira, Kroon, Gazzinelli and Bonjardim (2001) J. Biol. Chem. 276, 38353–38360]. In the present study, we show that VV infection provoked a sustained activation of both ERK1/2 and RSK2 (ribosomal S6 kinase 2). Our results also provide evidence that this pattern of kinase activation depends on virus multiplication and ongoing protein synthesis and is maintained independently of virus DNA synthesis. It is noteworthy that the VGF (VV growth factor), although involved, is not essential for prolonged ERK1/2 activation. Furthermore, our findings suggest that the VV-stimulated ERK1/2 activation also seems to require actin dynamics, microtubule polymerization and tyrosine kinase phosphorylation. The VV-stimulated pathway MEK/ERK1/2/RSK2 (where MEK stands for MAPK/ERK kinase) leads to phosphorylation of the ternary complex factor Elk-1 and expression of the early growth response (egr-1) gene, which kinetically paralleled the kinase activation. The recruitment of this pathway is biologically relevant, since its disruption caused a profound effect on viral thymidine kinase gene expression, viral DNA replication and VV multiplication. This pattern of sustained kinase activation after VV infection is unique. In addition, by connecting upstream signals generated at the cytoskeleton and by tyrosine kinase, the MEK/ERK1/2/RSK2 cascade seems to play a decisive role not only at early stages of the infection, i.e. post-penetration, but is also crucial to define the fate of virus progeny.

scholarly journals G Protein-Coupled Receptor-Mediated Mitogen-Activated Protein Kinase Activation through Cooperation of Gαq and Gαi Signals

2000 ◽  
Vol 20 (18) ◽  
pp. 6837-6848 ◽  
Author(s):  
Andree Blaukat ◽  
Ana Barac ◽  
Michael J. Cross ◽  
Stefan Offermanns ◽  
Ivan Dikic
Keyword(s):  
Protein Kinase ◽  
G Protein ◽  
Tyrosine Kinases ◽  
Synergistic Effects ◽  
Mitogen Activated Protein Kinase ◽  
General Mechanism ◽  
Mitogen Activated Protein ◽  
Novel Concept ◽  
G Protein Coupled ◽  
Stimulation Of

ABSTRACT G protein-coupled receptors (GPCRs) have been shown to stimulate extracellular regulated kinases (ERKs) through a number of linear pathways that are initiated by Gq/11 or Giproteins. We studied signaling to the ERK cascade by receptors that simultaneously activate both G protein subfamilies. In HEK293T cells, bradykinin B2 receptor (B2R)-induced stimulation of ERK2 and transcriptional activity of Elk1 are dependent on Gαq-mediated protein kinase C (PKC) and on Gαi-induced Ras activation, while they are independent of Gβγ subunits, phosphatidylinositol 3-kinase, and tyrosine kinases. Similar results were obtained with m1 and m3muscarinic receptors in HEK293T cells and with the B2R in human and mouse fibroblasts, indicating a general mechanism in signaling toward the ERK cascade. Furthermore, the bradykinin-induced activation of ERK is strongly reduced in Gαq/11-deficient fibroblasts. In addition, we found that constitutively active mutants of Gαq/11 or Gαi proteins alone poorly stimulate ERK2, whereas a combination of both led to synergistic effects. We conclude that dually coupled GPCRs require a cooperation of Gαi- and Gq/11-mediated pathways for efficient stimulation of the ERK cascade. Cooperative signaling by multiple G proteins thus might represent a novel concept implicated in the regulation of cellular responses by GPCRs.

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