Receptor tyrosine kinases as mediators of injury-induced bradykinin B1 receptor expression in rabbit aortic smooth muscle

The zoonotic Old World mammarenavirus Lassa (LASV) causes severe hemorrhagic fever with high mortality and morbidity in humans in endemic regions. The development of effective strategies to combat LASV infections is of high priority, given the lack of a licensed vaccine and restriction on available treatment to off-label use of ribavirin. A better understanding of the fundamental aspects of the virus’s life cycle would help to improve the development of novel therapeutic approaches. Host cell entry and restriction factors represent major barriers for emerging viruses and are promising targets for therapeutic intervention. In addition to the LASV main receptor, the extracellular matrix molecule dystroglycan (DG), the phosphatidylserine-binding receptors of the Tyro3/Axl/Mer (TAM), and T cell immunoglobulin and mucin receptor (TIM) families are potential alternative receptors of LASV infection. Therefore, the relative contributions of candidate receptors to LASV entry into a particular human cell type are a complex function of receptor expression and functional DG availability. Here, we describe the role of two receptor tyrosine kinases (RTKs), Axl and hepatocyte growth factor receptor (HGFR), in the presence and absence of glycosylated DG for LASV entry. We found that both RTKs participated in the macropinocytosis-related LASV entry and, regardless of the presence or absence of functional DG, their inhibition resulted in a significant antiviral effect.

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Bradykinin B1 receptor expression and function on T lymphocytes in active multiple sclerosis

Neurology ◽

10.1212/wnl.53.9.2087 ◽

1999 ◽

Vol 53 (9) ◽

pp. 2087-2087 ◽

Cited By ~ 50

Author(s):

A. Prat ◽

L. Weinrib ◽

B. Becher ◽

J. Poirier ◽

P. Duquette ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Lymphocytes ◽

Receptor Expression ◽

B1 Receptor ◽

Bradykinin B1 Receptor ◽

And Function ◽

Active Multiple Sclerosis

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Redox-dependent MAP kinase signaling by Ang II in vascular smooth muscle cells: role of receptor tyrosine kinase transactivation

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-164 ◽

2003 ◽

Vol 81 (2) ◽

pp. 159-167 ◽

Cited By ~ 72

Author(s):

Rhian M Touyz ◽

Montserrat Cruzado ◽

Fatiha Tabet ◽

Guoying Yao ◽

Steven Salomon ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Nadph Oxidase ◽

Map Kinase ◽

Vascular Smooth Muscle Cells ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

P38 Map Kinase ◽

Ang Ii

We investigated the role of receptor tyrosine kinases in Ang II-stimulated generation of reactive oxygen species (ROS) and assessed whether MAP kinase signaling by Ang II is mediated via redox-sensitive pathways. Production of ROS and activation of NADPH oxidase were determined by DCFDA (dichlorodihydrofluorescein diacetate; 2 μmol/L) fluorescence and lucigenin (5 μmol/L) chemiluminescence, respectively, in rat vascular smooth muscle cells (VSMC). Phosphorylation of ERK1/2, p38MAP kinase and ERK5 was determined by immunoblotting. The role of insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) was assessed with the antagonists AG1024 and AG1478, respectively. ROS bioavailability was manipulated with Tiron (105 mol/L), an intra cellular scavanger, and diphenylene iodinium (DPI; 106 mol/L), an NADPH oxidase inhibitor. Ang II stimulated NADPH oxidase activity and dose-dependently increased ROS production (p < 0.05). These actions were reduced by AG1024 and AG1478. Ang II-induced ERK1/2 phosphorylation (276% of control) was decreased by AG1478 and AG1024. Neither DPI nor tiron influenced Ang II-stimulated ERK1/2 activity. Ang II increased phosphorylation of p38 MAP kinase (204% of control) and ERK5 (278% of control). These effects were reduced by AG1024 and AG1478 and almost abolished by DPI and tiron. Thus Ang II stimulates production of NADPH-inducible ROS partially through transactivation of IGF-1R and EGFR. Inhibition of receptor tyrosine kinases and reduced ROS bioavaliability attenuated Ang II-induced phosphorylation of p38 MAP kinase and ERK5, but not of ERK1/2. These findings suggest that Ang II activates p38MAP kinase and ERK5 via redox-dependent cascades that are regulated by IGF-1R and EGFR transactivation. ERK1/2 regulation by Ang II is via redox-insensitive pathways.Key words: ERK1/2, p38MAP kinase, EGFR, IGF-1R, signal transduction.

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