Membrane progesterone receptor induces meiosis in Xenopus oocytes through endocytosis into signaling endosomes and interaction with APPL1 and Akt2

Nader, Nancy; Dib, Maya; Hodeify, Rawad; Courjaret, Raphael Jean; Elmi, Asha; Hammad, Ayat S.; Dey, Raja; Huang, Xin‐Yun; Machaca, Khaled

doi:10.1371/journal.pbio.3000901

Cited by 19 publications

(20 citation statements)

References 76 publications

(131 reference statements)

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“…Using transferrin as a marker for clathrin-dependent endocytosis we previously showed that the clathrin-dependent endocytosis inhibitor Pitstop2 (10 -5 M) effectively blocks transferrin uptake (Supp. Figure 3A) 19 (Fig. 3F).…”

Section: Orai1 Internalization Is Not Dependent On Flotillin or Clathmentioning

confidence: 91%

The carboxy terminal coiled-coil modulates Orai1 internalization during meiosis

Hodeify

Dib

Alcantara-Adap

et al. 2021

Sci Rep

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Regulation of Ca2+ signaling is critical for the progression of cell division, especially during meiosis to prepare the egg for fertilization. The primary Ca2+ influx pathway in oocytes is Store-Operated Ca2+ Entry (SOCE). SOCE is tightly regulated during meiosis, including internalization of the SOCE channel, Orai1. Orai1 is a four-pass membrane protein with cytosolic N- and C-termini. Orai1 internalization requires a caveolin binding motif (CBM) in the N-terminus as well as the C-terminal cytosolic domain. However, the molecular determinant for Orai1 endocytosis in the C-terminus are not known. Here we show that the Orai1 C-terminus modulates Orai1 endocytosis during meiosis through a structural motif that is based on the strength of the C-terminal intersubunit coiled coil (CC) domains. Deletion mutants show that a minimal C-terminal sequence after transmembrane domain 4 (residues 260–275) supports Orai1 internalization. We refer to this region as the C-terminus Internalization Handle (CIH). Access to CIH however is dependent on the strength of the intersubunit CC. Mutants that increase the stability of the coiled coil prevent internalization independent of specific mutation. We further used human and Xenopus Orai isoforms with different propensity to form C-terminal CC and show a strong correlation between the strength of the CC and Orai internalization. Furthermore, Orai1 internalization does not depend on clathrin, flotillin or PIP2. Collectively these results argue that Orai1 internalization requires both the N-terminal CBM and C-terminal CIH where access to CIH is controlled by the strength of intersubunit C-terminal CC.

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Section: Orai1 Internalization Is Not Dependent On Flotillin or Clathmentioning

confidence: 91%

The carboxy terminal coiled-coil modulates Orai1 internalization during meiosis

Hodeify

Dib

Alcantara-Adap

et al. 2021

Sci Rep

Self Cite

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“…However, frogs injected with hCG display robust production of androgens rather than P4; suggesting the possibility that androgens are the physiological MIS in Xenopus (Hammes, 2004; Lutz et al, 2001). P4 triggers oocyte maturation either by nuclear progesterone receptor (XPR) bound to the membrane (Bayaa et al, 2000) or by novel G‐protein coupled progestin receptors (mPR; Josefsberg Ben‐Yehoshua et al, 2007; Nader et al, 2020), while androgens function through the classical androgen receptors that are localized throughout oocytes, including within the plasma membrane (Lutz et al, 2003). Both P4 and androgens lower cAMP levels, downregulate PKA activity, and promote new protein synthesis, such as cyclins (B1, B2, B4, and B5), Ringo/Speedy—the non‐canonical activators of CDK1, and Mos—activator of MEK/ERK pathway (Eyers et al, 2005; Ferby et al, 1999; Ferrell, 1999; Haccard & Jessus, 2006b; Hammes, 2004; Meneau et al, 2020; Sadler & Maller, 1981; Wang & Liu, 2004).…”

Section: Oocyte Maturation and Erk Signaling Pathway In Nonmammalian ...mentioning

confidence: 99%

“…Mos, on the other hand, triggers ERK activation which in turn inactivates Myt1, the kinase that blocks Cdk1 activity (Palmer et al, 1998; Peter et al, 2002). Additionally, cAMP/PKA‐independent progesterone‐induced non‐genomic signaling is also documented (Nader et al, 2016), where a signaling endosome of mPRβ interacts with adaptor proteins and Akt2 to promote maturation (Nader et al, 2020). Thus, activation of MPF possibly proceeds through a parallel cAMP/PKA‐dependent and independent pathway and may converge to promote Xenopus oocyte maturation (Figure 3).…”

Section: Oocyte Maturation and Erk Signaling Pathway In Nonmammalian ...mentioning

confidence: 99%

“…Josefsberg Ben-Yehoshua et al, 2007;Nader et al, 2020), while androgens function through the classical androgen receptors that are localized throughout oocytes, including within the plasma membrane (Lutz et al, 2003). Both P4 and androgens lower cAMP levels, downregulate PKA activity, and promote new protein synthesis, such as cyclins (B1, B2, B4, and B5), Ringo/Speedy-the non-canonical activators of CDK1, and Mos-activator of MEK/ERK pathway (Eyers et al, 2005;Ferby et al, 1999;Ferrell, 1999;Haccard & Jessus, 2006b;Hammes, 2004;Meneau et al, 2020;Sadler & Maller, 1981;Wang & Liu, 2004).…”

Section: Oocyte Maturation In Nonmammalian Vertebratesmentioning

confidence: 99%

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Regulation of oocyte maturation: Role of conserved ERK signaling

Das

Arur

2022

Molecular Reproduction Devel

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During oogenesis, oocytes arrest at meiotic prophase I to acquire competencies for resuming meiosis, fertilization, and early embryonic development. Following this arrested period, oocytes resume meiosis in response to species‐specific hormones, a process known as oocyte maturation, that precedes ovulation and fertilization. Involvement of endocrine and autocrine/paracrine factors and signaling events during maintenance of prophase I arrest, and resumption of meiosis is an area of active research. Studies in vertebrate and invertebrate model organisms have delineated the molecular determinants and signaling pathways that regulate oocyte maturation. Cell cycle regulators, such as cyclin‐dependent kinase (CDK1), polo‐like kinase (PLK1), Wee1/Myt1 kinase, and the phosphatase CDC25 play conserved roles during meiotic resumption. Extracellular signal‐regulated kinase (ERK), on the other hand, while activated during oocyte maturation in all species, regulates both species‐specific, as well as conserved events among different organisms. In this review, we synthesize the general signaling mechanisms and focus on conserved and distinct functions of ERK signaling pathway during oocyte maturation in mammals, non‐mammalian vertebrates, and invertebrates such as Drosophila and Caenorhabditis elegans.

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“…Studies of multiple mPR knockouts in zebrafish have confirmed a role in both oocyte maturation and ovulation ( 176 ). In Xenopus oocytes, progesterone binding to mPRβ induced clathrin-dependent endocytosis of mPRβ into the signaling endosome, where mPR interacted transiently with APPL1 and Akt2 to induce meiosis ( 177 ). Additional physiological functions of mPRα include the promotion of sperm motility and the regulation of prolactin secretion.…”

Section: Membrane Progesterone Signalingmentioning

confidence: 99%

Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease

2021

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Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized (SRs) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.

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Membrane progesterone receptor induces meiosis in Xenopus oocytes through endocytosis into signaling endosomes and interaction with APPL1 and Akt2

Cited by 19 publications

References 76 publications

The carboxy terminal coiled-coil modulates Orai1 internalization during meiosis

The carboxy terminal coiled-coil modulates Orai1 internalization during meiosis

Regulation of oocyte maturation: Role of conserved ERK signaling

Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease

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