title: Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation.
abstract: BACKGROUND
  Cdc42 and Rac1, members of the Rho family of small GTPases, play critical roles in actin cytoskeleton regulation. We have shown previously that Rac1 is involved in regulation of platelet secretion and aggregation. However, the role of Cdc42 in platelet activation remains controversial. This study was undertaken to better understand the role of Cdc42 in platelet activation.
  
  
  RESULTS
  We utilized the Mx-cre;Cdc42(lox/lox) inducible mice with transient Cdc42 deletion to investigate the involvement of Cdc42 in platelet function. The Cdc42-deficient mice exhibited a significantly reduced platelet count than the matching Cdc42(+/+) mice. Platelets isolated from Cdc42(-/-), as compared to Cdc42(+/+), mice exhibited (a) diminished phosphorylation of PAK1/2, an effector molecule of Cdc42, (b) inhibition of filopodia formation on immobilized CRP or fibrinogen, (c) inhibition of CRP- or thrombin-induced secretion of ATP and release of P-selectin, (d) inhibition of CRP, collagen or thrombin induced platelet aggregation, and (e) minimal phosphorylation of Akt upon stimulation with CRP or thrombin. The bleeding times were significantly prolonged in Cdc42(-/-) mice compared with Cdc42(+/+) mice.
  
  
  CONCLUSIONS
  Our data demonstrate that Cdc42 is required for platelet filopodia formation, secretion and aggregation and therefore plays a critical role in platelet mediated hemostasis and thrombosis.
authors.affiliation: Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States of America. akbar@ohio.edu
authors.forename: Huzoor
authors.initials: H
authors.lastname: Akbar
authors.forename: Xun
authors.initials: X
authors.lastname: Shang
authors.forename: Rehana
authors.initials: R
authors.lastname: Perveen
authors.forename: Mark
authors.initials: M
authors.lastname: Berryman
authors.forename: Kevin
authors.initials: K
authors.lastname: Funk
authors.forename: James F
authors.initials: JF
authors.lastname: Johnson
authors.forename: Narendra N
authors.initials: NN
authors.lastname: Tandon
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005340:Fibrinogen / Q000494:pharmacology; D017353:Gene Deletion; D018390:Gene Targeting; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology; D013921:Thrombocytopenia / Q000378:metabolism / Q000473:pathology; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency* / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D010455:Peptides; D010980:Platelet Membrane Glycoproteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; D005340:Fibrinogen; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D013917:Thrombin; D020764:cdc42 GTP-Binding Protein