Pnma5 is essential to the progression of meiosis in mouse oocytes through a chain of phosphorylation

Abstract

PNMA (paraneoplastic antigen MA) family includes Pnma1–6. Although other members have been found to be involved in paraneoplastic neurological disorders, death receptor-dependent apoptosis, and tumorigenesis, Pnma5 was thought to be a female fertility factor, as indicated by one genome-wide study. But until now there have not been any further functional studies about Pnma5 in female meiosis. Our preliminary study indicated that Pnma5 might play important roles in meiosis. To further address this, Pnma5 was knocked down in in-vitro maturated (IVM) mouse oocytes, which are common models for mammalian female meiosis, by specific siRNA, and results showed that the loss of Pnma5 significantly delayed the progression of meiosis I and increased chromosome segregation errors during anaphase I. In in-vitro fertilization (IVF), Pnma5 knockdown caused significantly lower fertilization. To assess how it affects meiosis, Pnma5 knockdown was found to significantly decrease the stability of spindle microtubules and altered F-actin organization within actin cap regions, cause significantly abnormal mitochondria aggregation and lower ATP concentration. Next we have found that phosphorylation at Thr533 re-located Pnma5 strongly to spindles & cortex and was required for the phosphorylation of Akt and Gsk3β, while Src and Erk1/2 phosphorylation was required for the phosphorylation of Pnma5, indicating that phosphorylated Pnma5 is the active form and subsequently activates Akt and Gsk3β. Collectively this study suggests that Pnma5 is important for meiosis and is the pivot of Src→Erk1/2→Pnma5→Akt→Gsk3β pathway.

PNMA5 knockdown suppresses the proliferation, invasion, and metastasis of epithelial ovarian cancer cells

“…Our previous study confirmed the activity of the PNMA5 signaling pathway (Src→Erk1/2→PNMA5→Akt→GSK-3β), and the phosphorylation level of PNMA5 was related to upstream Src and Erk1/2 ( 8 ). In this study, HO8910 cells were treated with a Src protein inhibitor, and expression of PNMA5 and p-PNMA5 was detected by western blot analyses.…”

“…Src-family kinases (SFKs), which are involved in oncogenesis, are implicated in the promotion of tumor cell motility, proliferation, inhibition of apoptosis, invasion, and metastasis ( 23 ). Our previous study confirmed the phosphorylation level of PNMA5 was related to upstream Src and Erk1/2 ( 8 ). In this study, we used Src inhibitors to clarify the relationship between Src and PNMA5 in HO8910 cells and found that levels of phosphorylated PNMA5 decreased dramatically, with no change in PNMA5.…”

“…Lee et al showed that PNMA5 promotes apoptosis signaling in HeLa and MCF-7 cells and interacts synergistically with MOAP-1 through its N-terminal domain to promote apoptosis and chemosensitivity in human cancer cells ( 7 ). Our previous study suggested that PNMA5 is vital for meiosis and is pivotal for the Src→Erk1/2→PNMA5→Akt→glycogen synthase kinase-3β (GSK-3β) signaling pathway ( 8 ). These findings indicate that the PNMA5 gene may play an essential role in tumorigenesis and may be a useful therapeutic target.…”

Deciphering the Dark Proteome: Use of the Testis and Characterization of Two Dark Proteins

“…31 Recently, mouse pnma5 was shown to be involved in meiotic progression in oocytes by controlling the phosphorylation of two important kinases, PDK1 and Gsk3beta. 33 The authors also demonstrated that pnma5 knockdown mice exhibit abnormal oocyte fertilization.…”

“…The protein is highly enriched in the testis, particularly in germ cells up to meiosis. The expression of PNMA6E in only the human testis, and to a lower extent in the ovary and Fallopian tubes, favors a role in gametogenesis, similar to PNMA5, which is considered to be a female fertility factor 33 .However, this awaits further investigation. Page 23 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 uPE1 and MPs are highly expressed in the testis…”