Bone Morphogenetic Protein 2 Stimulates Noncanonical SMAD2/3 Signaling via the BMP Type 1A Receptor in Gonadotrope-Like Cells: Implications for FSH Synthesis

FSH is an essential regulator of mammalian reproduction. Its synthesis by pituitary gonadotrope cells is regulated by multiple endocrine and paracrine factors, including TGFβ superfamily ligands, such as the activins and inhibins. Activins stimulate FSH synthesis via transcriptional regulation of it...

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Veröffentlicht in:Endocrinology (Philadelphia) 2014-05, Vol.155 (5), p.1970-1981
Hauptverfasser: Wang, Ying, Ho, Catherine C, Bang, EunJin, Rejon, Carlis A, Libasci, Vanessa, Pertchenko, Pavel, Hébert, Terence E, Bernard, Daniel J
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container_end_page 1981
container_issue 5
container_start_page 1970
container_title Endocrinology (Philadelphia)
container_volume 155
creator Wang, Ying
Ho, Catherine C
Bang, EunJin
Rejon, Carlis A
Libasci, Vanessa
Pertchenko, Pavel
Hébert, Terence E
Bernard, Daniel J
description FSH is an essential regulator of mammalian reproduction. Its synthesis by pituitary gonadotrope cells is regulated by multiple endocrine and paracrine factors, including TGFβ superfamily ligands, such as the activins and inhibins. Activins stimulate FSH synthesis via transcriptional regulation of its β-subunit gene (Fshb). More recently, bone morphogenetic proteins (BMPs) were shown to stimulate murine Fshb transcription alone and in synergy with activins. BMP2 signals via its canonical type I receptor, BMPR1A (or activin receptor-like kinase 3 [ALK3]), and SMAD1 and SMAD5 to stimulate transcription of inhibitor of DNA binding proteins. Inhibitor of DNA binding proteins then potentiate the actions of activin-stimulated SMAD3 to regulate the Fshb gene in the gonadotrope-like LβT2 cell line. Here, we report the unexpected observation that BMP2 also stimulates the SMAD2/3 pathway in these cells and that it does so directly via ALK3. Indeed, this novel, noncanonical ALK3 activity is completely independent of ALK4, ALK5, and ALK7, the type I receptors most often associated with SMAD2/3 pathway activation. Induction of the SMAD2/3 pathway by ALK3 is dependent upon its own previous activation by associated type II receptors, which phosphorylate conserved serine and threonine residues in the ALK3 juxtamembrane glycine-serine-rich domain. ALK3 signaling via SMAD3 is necessary for the receptor to stimulate Fshb transcription, whereas its activation of the SMAD1/5/8 pathway alone is insufficient. These data challenge current dogma that ALK3 and other BMP type I receptors signal via SMAD1, SMAD5, and SMAD8 and not SMAD2 or SMAD3. Moreover, they suggest that BMPs and activins may use similar intracellular signaling mechanisms to activate the murine Fshb promoter in immortalized gonadotrope-like cells.
doi_str_mv 10.1210/en.2013-1741
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Its synthesis by pituitary gonadotrope cells is regulated by multiple endocrine and paracrine factors, including TGFβ superfamily ligands, such as the activins and inhibins. Activins stimulate FSH synthesis via transcriptional regulation of its β-subunit gene (Fshb). More recently, bone morphogenetic proteins (BMPs) were shown to stimulate murine Fshb transcription alone and in synergy with activins. BMP2 signals via its canonical type I receptor, BMPR1A (or activin receptor-like kinase 3 [ALK3]), and SMAD1 and SMAD5 to stimulate transcription of inhibitor of DNA binding proteins. Inhibitor of DNA binding proteins then potentiate the actions of activin-stimulated SMAD3 to regulate the Fshb gene in the gonadotrope-like LβT2 cell line. Here, we report the unexpected observation that BMP2 also stimulates the SMAD2/3 pathway in these cells and that it does so directly via ALK3. Indeed, this novel, noncanonical ALK3 activity is completely independent of ALK4, ALK5, and ALK7, the type I receptors most often associated with SMAD2/3 pathway activation. Induction of the SMAD2/3 pathway by ALK3 is dependent upon its own previous activation by associated type II receptors, which phosphorylate conserved serine and threonine residues in the ALK3 juxtamembrane glycine-serine-rich domain. ALK3 signaling via SMAD3 is necessary for the receptor to stimulate Fshb transcription, whereas its activation of the SMAD1/5/8 pathway alone is insufficient. These data challenge current dogma that ALK3 and other BMP type I receptors signal via SMAD1, SMAD5, and SMAD8 and not SMAD2 or SMAD3. 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Indeed, this novel, noncanonical ALK3 activity is completely independent of ALK4, ALK5, and ALK7, the type I receptors most often associated with SMAD2/3 pathway activation. Induction of the SMAD2/3 pathway by ALK3 is dependent upon its own previous activation by associated type II receptors, which phosphorylate conserved serine and threonine residues in the ALK3 juxtamembrane glycine-serine-rich domain. ALK3 signaling via SMAD3 is necessary for the receptor to stimulate Fshb transcription, whereas its activation of the SMAD1/5/8 pathway alone is insufficient. These data challenge current dogma that ALK3 and other BMP type I receptors signal via SMAD1, SMAD5, and SMAD8 and not SMAD2 or SMAD3. 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inhibitors</subject><subject>Smad2 Protein - genetics</subject><subject>Smad2 Protein - metabolism</subject><subject>Smad3 protein</subject><subject>Smad3 Protein - antagonists &amp; inhibitors</subject><subject>Smad3 Protein - genetics</subject><subject>Smad3 Protein - metabolism</subject><subject>Smad5 protein</subject><subject>Synthesis</subject><subject>Transcription activation</subject><subject>Transcription factors</subject><subject>Transcription, Genetic</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU1v1DAQhi0EokvhxhlZ4gAH0vorcdLbdks_pF2oSDlHiXe8dUnsYDuV9sfwX_FqF5AQnEYzevTo1bwIvabkhDJKTsGeMEJ5RqWgT9CMViLPJJXkKZqR3V0yJo_QixAe0iqE4M_RERMFoWVJZ-jHubOAV86P924DFqJR-Na7CMZihutohqlvIwT8yVnVWmeNantcr-YX7JTj2mxs2xu7wY-mxfEe8PnqFt9tR8B0jr-AgjE6j5Prytl27aJ3I2RL8w3wAvo-nOGbYeyTMhpnA9aJvayvcb21yRVMeIme6bYP8Oowj9HXy493i-ts-fnqZjFfZkpUVcy07sSa8gK0KCUo3SnOaaFFwbisuq7LVQkdk4TLTiiuBSlLRjrNi5wWBcs5P0bv997Ru-8ThNgMJqiUsLXgptDQnJZMCCaqhL79C31wk09fCA2nnEiSEuWJ-rCnlHcheNDN6M3Q-m1DSbOrrQHb7GprdrUl_M1BOnUDrH_Dv3pKwLs94Kbxf6rsoOJ7EuzaKW8sjB5C-JPynwF-AhmbrqE</recordid><startdate>20140501</startdate><enddate>20140501</enddate><creator>Wang, Ying</creator><creator>Ho, Catherine C</creator><creator>Bang, EunJin</creator><creator>Rejon, Carlis A</creator><creator>Libasci, Vanessa</creator><creator>Pertchenko, Pavel</creator><creator>Hébert, Terence E</creator><creator>Bernard, Daniel J</creator><general>Endocrine Society</general><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20140501</creationdate><title>Bone Morphogenetic Protein 2 Stimulates Noncanonical SMAD2/3 Signaling via the BMP Type 1A Receptor in Gonadotrope-Like Cells: Implications for FSH Synthesis</title><author>Wang, Ying ; 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Its synthesis by pituitary gonadotrope cells is regulated by multiple endocrine and paracrine factors, including TGFβ superfamily ligands, such as the activins and inhibins. Activins stimulate FSH synthesis via transcriptional regulation of its β-subunit gene (Fshb). More recently, bone morphogenetic proteins (BMPs) were shown to stimulate murine Fshb transcription alone and in synergy with activins. BMP2 signals via its canonical type I receptor, BMPR1A (or activin receptor-like kinase 3 [ALK3]), and SMAD1 and SMAD5 to stimulate transcription of inhibitor of DNA binding proteins. Inhibitor of DNA binding proteins then potentiate the actions of activin-stimulated SMAD3 to regulate the Fshb gene in the gonadotrope-like LβT2 cell line. Here, we report the unexpected observation that BMP2 also stimulates the SMAD2/3 pathway in these cells and that it does so directly via ALK3. Indeed, this novel, noncanonical ALK3 activity is completely independent of ALK4, ALK5, and ALK7, the type I receptors most often associated with SMAD2/3 pathway activation. Induction of the SMAD2/3 pathway by ALK3 is dependent upon its own previous activation by associated type II receptors, which phosphorylate conserved serine and threonine residues in the ALK3 juxtamembrane glycine-serine-rich domain. ALK3 signaling via SMAD3 is necessary for the receptor to stimulate Fshb transcription, whereas its activation of the SMAD1/5/8 pathway alone is insufficient. These data challenge current dogma that ALK3 and other BMP type I receptors signal via SMAD1, SMAD5, and SMAD8 and not SMAD2 or SMAD3. 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subjects Activin
Activins - antagonists & inhibitors
Activins - metabolism
Animals
Binding
Bone morphogenetic protein 2
Bone Morphogenetic Protein 2 - agonists
Bone Morphogenetic Protein 2 - antagonists & inhibitors
Bone Morphogenetic Protein 2 - genetics
Bone Morphogenetic Protein 2 - metabolism
Bone morphogenetic protein receptor type I
Bone Morphogenetic Protein Receptors, Type I - agonists
Bone Morphogenetic Protein Receptors, Type I - antagonists & inhibitors
Bone Morphogenetic Protein Receptors, Type I - genetics
Bone Morphogenetic Protein Receptors, Type I - metabolism
Bone morphogenetic proteins
Cell Line
Deoxyribonucleic acid
DNA
Follicle Stimulating Hormone, beta Subunit - biosynthesis
Follicle Stimulating Hormone, beta Subunit - genetics
Follicle Stimulating Hormone, beta Subunit - metabolism
Follicle-stimulating hormone
Gene regulation
Gene Silencing
Genes, Reporter
Glycine
Gonadotrophs - metabolism
Humans
Intracellular signalling
Kinases
Mice
Paracrine signalling
Phosphorylation
Pituitary
Pituitary (anterior)
Protein Processing, Post-Translational
Proteins
Receptors
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
RNA, Small Interfering
Serine
Signal Transduction
Smad2 protein
Smad2 Protein - antagonists & inhibitors
Smad2 Protein - genetics
Smad2 Protein - metabolism
Smad3 protein
Smad3 Protein - antagonists & inhibitors
Smad3 Protein - genetics
Smad3 Protein - metabolism
Smad5 protein
Synthesis
Transcription activation
Transcription factors
Transcription, Genetic
title Bone Morphogenetic Protein 2 Stimulates Noncanonical SMAD2/3 Signaling via the BMP Type 1A Receptor in Gonadotrope-Like Cells: Implications for FSH Synthesis
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