title: p21-activated kinase 1 activity is required for histone H3 Ser10phosphorylation and chromatin condensation in mouse oocyte meiosis.
abstract: p21-activated kinase 1 (Pak1) is essential for a variety of cellular events, including gene transcription, cytoskeletal organisation, cell proliferation and apoptosis. Pak1 is activated upon autophosphorylation on many amino residues; in particular, phosphorylation on Thr423maintains maximal Pak1 activation. In the present study we investigated the protein expression, subcellular localisation and function of Pak1 phosphorylated on Thr423(pPak1Thr423) in mouse oocytes. pPak1Thr423was detected upon meiotic resumption and localised on the condensing chromatin. Thr423phosphorylation was markedly suppressed by the Pak1 ATP-competitive inhibitor PF-3758309, but not by the allosteric inhibitors IPA-3 (2.5 μM and 10μM) (1, 1'-dithiobis-2-naphthalenol) and TAT-PAK18 (10 μM), which prevent the binding of Pak1 to its upstream activators GTPase Cdc42/Rac and Pak-interacting exchange factor (PIX), respectively, implying that Pak1 activation may be independent of GTPase and PIX in oocyte meiosis. Inhibition of Pak1 activation concomitantly restrained histone H3 phosphorylation on Ser10and consequently inhibited chromatin condensation; however, this phenotype was reversed by concomitant administration of the Pak1 activator FTY720. The changes in the pattern of expression of phosphorylated extracellular signal-regulated kinase 1/2 in response to PF-3758309 or FTY720 were the same as seen for pPak1Thr423. These results show that activated Pak1 regulates chromatin condensation by promoting H3 Ser10phosphorylation in oocytes after the resumption of meiotic progression.
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Biospecimen and Clinical Data Repository, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Experimental Center for Basic Medical Teaching, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Weng
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
mesh_terms: D000818:Animals; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D008540:Meiosis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C576607:Arhgef7 protein, mouse; C581598:Cdc42 protein, mouse; D002843:Chromatin; D006657:Histones; C550923:PF 3758309; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D064067:Rho Guanine Nucleotide Exchange Factors; D012694:Serine; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D000068876:Fingolimod Hydrochloride