title: Proprotein convertase 5/6 cleaves platelet-derived growth factor A in the human endometrium in preparation for embryo implantation.
abstract: Establishment of endometrial receptivity is vital for successful embryo implantation. Proprotein convertase 5/6 (referred to as PC6) is up-regulated in the human endometrium specifically at the time of epithelial receptivity. PC6, a serine protease of the proprotein convertase family, plays an important role in converting precursor proteins into their active forms through specific proteolysis. The proform of platelet-derived growth factor A (pro-PDGFA) requires PC cleavage to convert to the active-PDGFA. We investigated the PC6-mediated activation of PDGFA in the human endometrium during the establishment of receptivity. Proteomic analysis identified that the pro-PDGFA was increased in the conditioned medium of HEC1A cells in which PC6 was stably knocked down by small interfering RNA (PC6-siRNA). Western blot analysis demonstrated an accumulation of the pro-PDGFA but a reduction in the active-PDGFA in PC6-siRNA cell lysates and medium compared with control. PC6 cleavage of pro-PDGFA was further confirmed in vitro by incubation of recombinant pro-PDGFA with PC6. Immunohistochemistry revealed cycle-stage-specific localization of the active-PDGFA in the human endometrium. During the non-receptive phase, the active-PDGFA was barely detectable. In contrast, it was localized specifically to the apical surface of the luminal and glandular epithelium in the receptive phase. Furthermore, the active-PDGFA was detected in uterine lavage with levels being significantly higher in the receptive than the non-receptive phase. We thus identified that the secreted PDGFA may serve as a biomarker for endometrial receptivity. This is also the first study demonstrating that the active-PDGFA localizes to the apical surface of the endometrium during receptivity.
authors.affiliation: Implantation and Placental Development Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia Monash University, Clayton, Victoria 3168, Australia sarah.paule@mimr-phi.org guiying.nie@mimr-phi.org.
authors.forename: Sarah
authors.initials: S
authors.lastname: Paule
authors.affiliation: Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nebl
authors.affiliation: Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Webb
authors.affiliation: Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia Women's and Children's Programme, Monash Health, Clayton, Victoria 3168, Australia Monash IVF, Clayton, Victoria 3168, Australia.
authors.forename: Beverley
authors.initials: B
authors.lastname: Vollenhoven
authors.affiliation: Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia Women's and Children's Programme, Monash Health, Clayton, Victoria 3168, Australia Monash IVF, Clayton, Victoria 3168, Australia.
authors.forename: Luk J F
authors.initials: LJ
authors.lastname: Rombauts
authors.affiliation: Implantation and Placental Development Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia Monash University, Clayton, Victoria 3168, Australia sarah.paule@mimr-phi.org guiying.nie@mimr-phi.org.
authors.forename: Guiying
authors.initials: G
authors.lastname: Nie
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D010064:Embryo Implantation / Q000502:physiology; D004622:Embryo, Mammalian; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D046910:Fertile Period / Q000235:genetics* / Q000378:metabolism; D005498:Follicular Phase / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D045702:Proprotein Convertase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; C075278:platelet-derived growth factor A; D045702:Proprotein Convertase 5
keywords: endometrial receptivity; implantation; platelet-derived growth factor A; protein convertase 5/6; proteomics