Le récepteur de la thrombine et ses implications dans la prolifération des cellules vasculaires

Abstract

The serine protease thrombin, most widely known for its pivotal role in blood coagulation, is just beginning to be recognized as an important initiator of post-clotting processes and growth stimulator. Thrombin is a potent mitogen for vascular smooth muscle (VSM) cells and fibroblasts. A great deal of attention has been directed to the proliferative response of VSM cells and its regulation, as alteration of growth is the basis of atherogenesis and clinical complications of ten observed following angioplasty and the implantation of vascular grafts. Expression cloning and sequencing of a thrombin receptor cDNA from a human megakaryocytic line and hamster fibroblasts has provided a framework to study the molecular mechanisms of thrombin action. The thrombin receptor is a member of the seven membrane-spanning receptor family that stimulates intracellular signaling pathways via G proteins. Thrombin activation of its receptor occurs by a unique proteolytic mechanism whereby cleavage at a defined site in the N-terminal ectodomain unmasks a tethered ligand. Accordingly, the receptor can be fully activated by synthetic peptides (greater-than-or-equal-to corresponding to the sequence of the receptor's 'built-in' ligand. At least two G protein signaling systems are functionally coupled to the receptor : (1) a Phospholipase C / Protein kinase C pathway (via a G(q) protein), and (2) a G(i)-coupled pathway, whose activation is essential for cell cycle re-entry. Consequently, several kinase cascades, common to those activated by receptor tyrosine kinases, are initiated by thrombin which lead to phosphorylation of key cellular components involved in signaling cell differentiation and growth.