title: PDK1 regulates platelet activation and arterial thrombosis.
abstract: The effects of phosphoinositide-dependent protein kinase 1 (PDK1), a master kinase in the phosphoinositide 3-kinase/Akt pathway, on platelet activation are unknown. Accordingly, platelet-specific PDK1-deficient mice were characterized to elucidate the platelet-related function(s) of PDK1. We found that PDK1 deficiency caused mild thrombocytopenia. The aggregation of PDK1(-/-) platelets was diminished in response to low levels of thrombin, U46619, and adenosine 5'-diphosphate. Further results demonstrated that PDK1 regulates thrombin-induced platelet activation by affecting αIIbβ3-mediated outside-in signaling. This result provided an explanation for the diminished spreading of PDK1(-/-) platelets on immobilized fibrinogen (Fg) and the decreased rate of clot retraction in platelet-rich plasma (PRP) containing PDK1(-/-) platelets. PDK1 deficiency diminished agonist-induced Akt Ser473 phosphorylation and thoroughly abolished Akt Thr308 and Gsk3β Ser9 phosphorylation in response to agonist treatment and platelet spreading, respectively. A Gsk3β inhibitor fully restored the aggregation of PDK1(-/-) platelets in response to low levels of thrombin, normal spreading of PDK1(-/-) platelets on Fg, and normal clot retraction in PRP containing PDK1(-/-) platelets. Those results indicated that Gsk3β is one of the major downstream effectors of PDK1 in thrombin-induced platelet activation and αIIbβ3-mediated outside-in signaling. In addition, in vivo data demonstrated that PDK1 is an important regulator in arterial thrombosis formation.
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai, China.
authors: Xue
authors: X
authors: Chen
authors: Yue
authors: Y
authors: Zhang
authors: Yanhua
authors: Y
authors: Wang
authors: Ding
authors: D
authors: Li
authors: Lin
authors: L
authors: Zhang
authors: Kemin
authors: K
authors: Wang
authors: Xinping
authors: X
authors: Luo
authors: Zhongzhou
authors: Z
authors: Yang
authors: Yi
authors: Y
authors: Wu
authors: Junling
authors: J
authors: Liu
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D003018:Clot Retraction / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000235:genetics* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014662:Vasoconstrictor Agents; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017346:Protein Serine-Threonine Kinases; D013917:Thrombin