title: p21 activated kinase signaling coordinates glycoprotein receptor VI-mediated platelet aggregation, lamellipodia formation, and aggregate stability under shear.
abstract: OBJECTIVE
  Rho GTPase proteins play a central role in regulating the dynamics of the platelet actin cytoskeleton. Yet, little is known regarding how Rho GTPase activation coordinates platelet activation and function. In this study, we aimed to characterize the role of the Rho GTPase effector, p21 activated kinase (PAK), in platelet activation, lamellipodia formation, and aggregate formation under shear.
  
  
  RESULTS
  Stimulation of platelets with the glycoprotein receptor VI agonist, collagen-related peptide, rapidly activated PAK in a time course preceding phosphorylation of PAK substrates, LIM domain kinase LIMK1 and the MAPK/ERK kinase MEK, and the subsequent activation of MAPKs and Akt. Pharmacological inhibitors of PAK blocked signaling events downstream of PAK and prevented platelet secretion as well as platelet aggregation in response to collagen-related peptide. PAK inhibitors also prevented PAK activation and platelet spreading on collagen surfaces. PAK was also required for the formation of platelet aggregates and to maintain aggregate stability under physiological shear flow conditions.
  
  
  CONCLUSIONS
  These results suggest that PAK serves as an orchestrator of platelet functional responses after activation downstream of the platelet collagen receptor, glycoprotein receptor VI.
authors: Department of Biomedical Engineering, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA. aslanj@ohsu.edu
authors: Joseph E
authors: JE
authors: Aslan
authors: Asako
authors: A
authors: Itakura
authors: Kristina M
authors: KM
authors: Haley
authors: Garth W
authors: GW
authors: Tormoen
authors: Cassandra P
authors: CP
authors: Loren
authors: Sandra M
authors: SM
authors: Baker
authors: Jiaqing
authors: J
authors: Pang
authors: Jonathan
authors: J
authors: Chernoff
authors: Owen J T
authors: OJ
authors: McCarty
mesh_terms: D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D002352:Carrier Proteins / Q000494:pharmacology; D048430:Cell Shape; D004789:Enzyme Activation; D006801:Humans; D054461:Lim Kinases / Q000097:blood; D020930:MAP Kinase Kinase Kinases / Q000097:blood; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011554:Pseudopodia / Q000187:drug effects / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D013997:Time Factors; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000097:blood*
chemical_list: D002352:Carrier Proteins; D010455:Peptides; D010980:Platelet Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; C515892:LIMK1 protein, human; D054461:Lim Kinases; D054462:p21-Activated Kinases; D020930:MAP Kinase Kinase Kinases
keywords: cell signaling; platelet; signal transduction
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