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Role of PC6 in regulating embryo implantation and fertility
Summary
We are determining the molecular mechanisms of PC6 action in the uterus for embryo implantation. We are also investigating the clinical implications of uterine PC6 expression in evaluating uterine receptivity, uterine fertility and infertility.
Description
Proprotein convertases (PCs) are a family of serine proteases which convert numerous important proteins from their initially synthesised non-active precursors into bioactive forms.
PCs are important regulatory molecules in generating a large number of tissue-specific and functionally important bioactive proteins. These proteinsinclude growth factors, peptide hormones and adhesion molecules. PCs are therefore regarded as critical “master switch” molecules and recognised as promising targets for therapeutic applications.
We have discovered that PC6, one member of the PC family, plays a critical role in the uterus for embryo implantation. PC6 is up-regulated in the uterus specifically at implantation in association with epithelial differentiation and stromal cell decidualization. Knockdown of PC6 in the uterus completely inhibits embryo implantation in mice.
For such a vital regulatory molecule, understanding the mechanisms of its action is significant. As it is a protease, identifying its substrates is the key. We are using a number of approaches, including cell culture, animal models, molecular biology, siRNA and proteomic techniques, to identify the physiological substrates of PC6 in the uterus that are important for implantation.
Further, the production of PC6 in the human uterus is associated with uterine receptivity, fertility and infertility. We are investigating the potential clinical implications of these observations, including developing a diagnostic marker for evaluating uterine receptivity for implantation, especially in the IVF procedures.
Funding
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National Health and Medical Research Council
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Contraceptive Research and Development Agency (CONRAD), USA
Outcomes
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We have identified a group of proteins which are tightly regulated by PC6 in the uterus. These PC6 substrates have never been characterised before. This provides important insight into the mechanisms PC6 action in the uterus for embryo implantation.
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We have established a proteomic method as a novel and unbiased approach to identify PC-regulated proteins of physiological relevance.
Selected Publications
Aljofan M, Singh H, Ho H, Xie S, Zhu Y, Sun Z, Guo X, Wang J and Nie G (2012) Inhibition of proprotein convertase 5/6 activity: potential for non-hormonal women-centered contraception. Contraception 85: 602-610
Ho H, Singh H, Aljofan M and Nie G (2012) A high-throughput in vitro model of human embryo attachment. Fertil Steril 97: 974-978
Singh H, Heng S, Nicholls PN, Li Y, Tai L, Jobling T, Salamonsen LA and Nie G (2012) Proprotein convertases in post-menopausal endometrial cancer: distinctive regulation and non-invasive diagnosis. Biochem Biophys Res Commun 419: 809-814
Paule S, Nie G (2011) Cytoskeletal remodelling proteins identified in fetal-maternal interface in pregnant women and rhesus monkeys. J Mol Histol 42:161-166
Nicholls PK, Sun Z, Heng S, Li Y, Wang J, Nie G (2011). Embryo implantation is closely associated with dynamic expression of proprotein convertase 6 in the rabbit uterus. Reprod Biol Endocrinol 9: 1-10
Paule S, Meehan K, Rainczuk A, Stephens AN, Nie G (2011) Combination of hydrogel nanoparticles and proteomics to reveal secreted proteins associated with decidualization of human uterine stromal cells. Proteome Sci 9: 1-6
Heng S, Cervero A, Simon C, Stephens AN, Li Y, Zhang J, Paule S, Rainczuk A, Singh H, Quinonero A, Tapia A, Velasquez L, Salamonsen L, Rombauts LJF and Nie G (2011) Proprotein convertase 5/6 is critical for embryo implantation in women: regulating receptivity by cleaving EBP50, modulating ezrin binding and membrane-cytoskeletal interactions. Endocrinology 52: 5041-5052
Heng S, Hannan NJ, Rombauts L, Salamonsen LA, Nie G (2011) PC6 levels in uterine lavage are closely associated with uterine receptivity and significantly lower in a sub-group of women with unexplained infertility. Hum Reprod 26: 840-846
Nie G and Stephens AN (2011) A proteomic protocol to identify physiological substrates of proprotein convertases. Methods Mol Biol 768: 325-341
Heng S, Paule S, Hardman B, Li Y, Singh H, Rainczuk A, Stephens AN and Nie G (2010) Posttranslational activation of bone morphogenetic protein 2 is mediated by proprotein convertase 6 during decidualization for pregnancy establishment. Endocrinology 151: 3909-3917
Paule S, Kilpatrick LM, Li Y, Stephens AN and Nie G (2010) A proteomic approach in identifying novel cytoskeletal remodelling proteins during decidualization of uterine stromal cells. J Proteome Res 9: 5739-4757
Kilpatrick LM, Stephens AN, Hardman BM, Salamonsen LA, Li Y, Stanton PG and Nie G (2009) Proteomic identification of caldesmon as a physiological substrate of proprotein convertase 6 in human uterine decidual cells essential for pregnancy establishment. J Proteome Res 8: 4983-4992
Nie G, Dimitriadis E, Hannan NJ, Paiva P and Salamonsen LA (2009) Local regulation of implantation at the human fetal-maternal interface. Int J Dev Biol 54: 313-322
Nie G, Kilpatrick LM, Stephens AN, Chen JC, Stanton P, and Salamonsen LA (2008) Proteomic identification of proprotein convertase 6 substrates in human endometrial stromal cells during decidualization. Biol Reprod 78: p57
Freyer C, Kilpatrtick L, Salamonsen LA and Nie G (2007) Pro-protein convertases other than PC6 are not tightly regulated for implantation in the human endometrium. Reproduction 133: 1189-1197
Okada H, Nie G, Salamonsen LA (2005) Requirement for proprotein convertase 5/6 during decidualization of human endometrial stromal cells in vitro. J Clin Endocrinol Metab 90: 1028-1034
Nie G, Li Y, Wang M, Liu YX, Findlay JK, Salamonsen LA (2005) Inhibiting uterine proprotein convertase 6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility. Biol Reprod 72: 1029-1036
Nie G, Li Y, Minoura H, Findlay JK, Salamonsen LA (2003) Specific and transient up-regulation of proprotein convertase 6 (PC6) at the site of embryo implantation and identification of a uterine-specific transcript in mouse uterus during early pregnancy. Biol Reprod 68: 439-447