Thrombin-mediated Proteoglycan Synthesis Utilizes Both Protein-tyrosine Kinase and Serine/Threonine Kinase Receptor Transactivation in Vascular Smooth Muscle Cells

Abstract

Background: GPCR transactivation of PTKRs and TGF-␤Rs mediates proteoglycan synthesis in human VSMC. Results: Transactivation of TGF-␤Rs is integrin-dependent, and inhibition of both transactivation pathways blocks proteoglycan synthesis. Conclusion: GPCR utilize transactivation pathways and not classical signaling in proteoglycan synthesis. Significance: GPCR transactivation of receptor kinase pathways may be broader and more significant than previously recognized.

The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

“…A third important and incompletely understood event downstream of GPCR activation is the transactivation of receptor tyrosine kinases (RTKs, e.g., epidermal growth factor receptor (EGFR)) and, more recently, receptor serine/threonine kinases (RS/TKs, e.g., transforming growth factor β type I receptor (TβRI); (Burch et al 2013)). RTK transactivation (Figure 2c), also known as triple-membrane-pass signalling, may occur roughly as follows: a ligandactivated GPCR activates the G-protein, causing activation of an RTK transactivation mediator (e.g., dissociation of Gβγ, followed by its activation of the non-membrane tyrosine kinase Src).…”

Assessing the Role of Gαq/11 in Cellular Responses: An Analysis of Investigative Tools

“…Nevertheless, a small molecule inhibitor is required in this area and potentially a modern drug discovery program directed at the YM-254890 or UBO-QIC structures might serve as a starting point. The need for a potent and efficacious agent is exemplified in the area of GPCR transactivation signalling where there is very little knowledge of the role of G proteins either in the long established transactivation of protein tyrosine kinase receptors or the more recently identified transactivation of serine/threonine kinase receptors [3,4,26]. The role of G proteins has not been described and potentially a common G protein dependent mechanism might represent a novel therapeutic target to block all of the responses attributable to GPCR transactivation signalling [27].…”

“…The former initiates' calcium release from the sarcoplasmic reticulum and the latter activates several members of the Protein Kinase C (PKC) family. As well as this classic paradigm, GPCRs also transactivate cell surface transmembrane kinase receptors of the protein tyrosine and protein serine/threonine kinase families specific examples of which are the Epidermal Growth Factor Receptor (EGFR) and Type I Transforming Growth Factor-β Receptor (TβRI), respectively [3,4]. Transactivation of these polyfunctional receptors enormously expands the range of GPCR responses to include cell growth and the synthesis of multiple extracellular matrix components and determines a role for GPCRs in physiology and pathophysiology [5,6].…”

The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier

“…Our laboratory has described a phenomenon in which thrombin acting through its GPCR, protease-activated receptor-1 (PAR-1), stimulated TGFBR1 mediated carboxy-terminal Smad transcription factor phosphorylation and the synthesis of proteoglycans in vascular smooth muscle cells (VSMCs) [33]. By analogy with the GPCR to protein tyrosine kinase activation, we have applied the term transactivation to this response [27,33,38]. Earlier, several groups identified a similar process but did not apply the term transactivation [39][40][41][42].…”