Protease activated receptor-1 mediated dual kinase receptor transactivation stimulates the expression of glycosaminoglycan synthesizing genes

Kamato, Danielle, Thach, Lyna, Getachew, Robel, Burch, Micah, Hollenberg, Morley D., Zheng, Wenhua, Little, Peter J. and Osman, Narin (2016) Protease activated receptor-1 mediated dual kinase receptor transactivation stimulates the expression of glycosaminoglycan synthesizing genes. Cellular Signalling, 28 1: 110-119. doi:10.1016/j.cellsig.2015.11.003

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Author Kamato, Danielle
Thach, Lyna
Getachew, Robel
Burch, Micah
Hollenberg, Morley D.
Zheng, Wenhua
Little, Peter J.
Osman, Narin
Title Protease activated receptor-1 mediated dual kinase receptor transactivation stimulates the expression of glycosaminoglycan synthesizing genes
Journal name Cellular Signalling   Check publisher's open access policy
ISSN 0898-6568
1873-3913
Publication date 2016-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.cellsig.2015.11.003
Open Access Status File (Author Post-print)
Volume 28
Issue 1
Start page 110
End page 119
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Abstract G protein-coupled receptors (GPCR) are one of the most important targets for therapeutics due to their abundance and diversity. The G protein-coupled receptor for thrombin can transactivate protein tyrosine kinase receptors (PTKR) and we have recently established that it can also transactivate serine/threonine kinase receptors (S/TKR). A comprehensive knowledge of the signalling pathways that GPCR transactivation elicits is necessary to fully understand the implications of both GPCR activation and the impact of target drugs. Here, we demonstrate that thrombin elicits dual transactivation-dependent signalling pathways to stimulate mRNA expression of glycosaminoglycan synthesizing enzymes chondroitin 4-O-sulfotransferase 1 and chondroitin sulfate synthase 1. The PTKR mediated response involves matrix metalloproteinases and the phosphorylation of the MAP kinase Erk. The S/TKR mediated response differs markedly and involves the phosphorylation of Smad2 carboxy terminal serine residues and does not involve matrix metalloproteinases. This work shows that all of the thrombin mediated signalling to glycosaminoglycan synthesizing enzyme gene expression occurs via transactivation-dependent pathways and does not involve transactivation-independent signalling. These findings highlight the complexity of thrombin-mediated transactivation signalling and the broader implications of GPCR targeted therapeutics.
Keyword Thrombin
Transforming growth factor beta
Transactivation-dependent
Glycosaminoglycan enzymes
Smad linker region
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Pharmacy Publications
 
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