title: Thrombin-mediated proteoglycan synthesis utilizes both protein-tyrosine kinase and serine/threonine kinase receptor transactivation in vascular smooth muscle cells.
abstract: G protein-coupled receptor signaling is mediated by three main mechanisms of action; these are the classical pathway, β-arrestin scaffold signaling, and the transactivation of protein-tyrosine kinase receptors such as those for EGF and PDGF. Recently, it has been demonstrated that G protein-coupled receptors can also mediate signals via transactivation of serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Atherosclerosis is characterized by the development of lipid-laden plaques in blood vessel walls. Initiation of plaque development occurs via low density lipoprotein retention in the neointima of vessels due to binding with modified proteoglycans secreted by vascular smooth muscle cells. Here we show that transactivation of protein-tyrosine kinase receptors is mediated by matrix metalloproteinase triple membrane bypass signaling. In contrast, serine/threonine kinase receptor transactivation is mediated by a cytoskeletal rearrangement-Rho kinase-integrin system, and both protein-tyrosine kinase and serine/threonine kinase receptor transactivation concomitantly account for the total proteoglycan synthesis stimulated by thrombin in vascular smooth muscle. This work provides evidence of thrombin-mediated proteoglycan synthesis and paves the way for a potential therapeutic target for plaque development and atherosclerosis.
authors: Diabetes Complications Laboratory, Royal Melbourne Institute of Technology University, Bundoora, Victoria 3004, Australia.
authors: Micah L
authors: ML
authors: Burch
authors: Robel
authors: R
authors: Getachew
authors: Narin
authors: N
authors: Osman
authors: Mark A
authors: MA
authors: Febbraio
authors: Peter J
authors: PJ
authors: Little
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans / Q000096:biosynthesis*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D006490:Hemostatics; D016023:Integrins; D011509:Proteoglycans; D043562:Receptors, G-Protein-Coupled; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D012694:Serine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D013917:Thrombin; D020782:Matrix Metalloproteinases