title: Loss of oligophrenin1 leads to uncontrolled Rho activation and increased thrombus formation in mice.
abstract: BACKGROUND
  Platelet cytoskeletal reorganization is essential for platelet adhesion and thrombus formation in hemostasis and thrombosis. The Rho GTPases RhoA, Rac1 and Cdc42 are the main players in cytoskeletal dynamics of platelets and induce filopodia and lamellipodia formation and actin polymerization to strongly increase the platelet surface upon activation. Moreover, they are important for platelet secretion, integrin activation and arterial thrombus formation.
  
  
  OBJECTIVE
  Rho GTPases are regulated by GTPase-activating proteins (GAPs) that stimulate their GTPase activity to terminate Rho signaling. The regulation of Rho GTPase activity in platelets is not well defined. Recently, we identified oligophrenin1 (OPHN1), a RhoGAP in platelets that exhibits strong GTPase-stimulating activity towards RhoA, Cdc42 and Rac1.
  
  
  RESULTS
  In the present study we show for the first time, that deficiency of OPHN1 led to abnormal Rho activation and increased platelet cytoskeletal reorganization, including cell adhesion and lamellipodia formation on fibrinogen. Furthermore, platelets from ophn1(-/-) mice showed enhanced susceptibility to platelet activation with alterations in actin distribution and early release of granules. Platelet activation was enhanced following GPVI and PAR4 stimulation. This translated into elevated platelet thrombus formation and promoted arterial thrombosis under low shear conditions with altered hemostasis, as detected by tail bleeding time.
  
  
  CONCLUSIONS
  The results of the present study identified OPHN1 as an important regulator of platelet cytoskeletal reorganization and demonstrate that abnormal regulation of Rho proteins leads to increased platelet adhesion and thrombus formation under low shear conditions in vitro and in vivo, suggesting a prothrombotic phenotype of mice critical for acute thrombotic occlusions.
authors.affiliation: Medizinische Klinik III, Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Fotinos
authors.forename: M
authors.initials: M
authors.lastname: Klier
authors.forename: N S
authors.initials: NS
authors.lastname: Gowert
authors.forename: P
authors.initials: P
authors.lastname: Münzer
authors.forename: C
authors.initials: C
authors.lastname: Klatt
authors.forename: S
authors.initials: S
authors.lastname: Beck
authors.forename: O
authors.initials: O
authors.lastname: Borst
authors.forename: P
authors.initials: P
authors.lastname: Billuart
authors.forename: M
authors.initials: M
authors.lastname: Schaller
authors.forename: F
authors.initials: F
authors.lastname: Lang
authors.forename: M
authors.initials: M
authors.lastname: Gawaz
authors.forename: M
authors.initials: M
authors.lastname: Elvers
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000201:enzymology*; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics; D003599:Cytoskeleton / Q000201:enzymology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D020690:GTPase-Activating Proteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000097:blood; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D015539:Platelet Activation; D011554:Pseudopodia / Q000201:enzymology; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D013997:Time Factors; D020764:cdc42 GTP-Binding Protein / Q000097:blood; D020830:rac1 GTP-Binding Protein / Q000097:blood; D020741:rho GTP-Binding Proteins / Q000097:blood*; D020742:rhoA GTP-Binding Protein
chemical_list: C581598:Cdc42 protein, mouse; D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse; C484602:Rac1 protein, mouse; C526380:RhoA protein, mouse; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: Rho GTPases; cytoskeleton; oligophrenin 1, mouse; platelet activation; thrombosis