The 3'-phosphoadenosine 5'-phosphosulfate transporters, PAPST1 and 2, contribute to the maintenance and differentiation of mouse embryonic stem cells
Recently, we have identified two 3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporters (PAPST1 and PAPST2), which contribute to PAPS transport into the Golgi, in both human and Drosophila. Mutation and RNA interference (RNAi) of the Drosophila PAPST have shown the importance of PAPST-d...
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| creator | Sasaki, Norihiko Hirano, Takuya Ichimiya, Tomomi Wakao, Masahiro Hirano, Kazumi Kinoshita-Toyoda, Akiko Toyoda, Hidenao Suda, Yasuo Nishihara, Shoko |
| description | Recently, we have identified two 3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporters (PAPST1 and PAPST2), which contribute to PAPS transport into the Golgi, in both human and Drosophila. Mutation and RNA interference (RNAi) of the Drosophila PAPST have shown the importance of PAPST-dependent sulfation of carbohydrates and proteins during development. However, the functional roles of PAPST in mammals are largely unknown. Here, we investigated whether PAPST-dependent sulfation is involved in regulating signaling pathways required for the maintenance of mouse embryonic stem cells (mESCs), differentiation into the three germ layers, and neurogenesis. By using a yeast expression system, mouse PAPST1 and PAPST2 proteins were shown to have PAPS transport activity with an apparent K(m) value of 1.54 microM or 1.49 microM, respectively. RNAi-mediated knockdown of each PAPST induced the reduction of chondroitin sulfate (CS) chain sulfation as well as heparan sulfate (HS) chain sulfation, and inhibited mESC self-renewal due to defects in several signaling pathways. However, we suggest that these effects were due to reduced HS, not CS, chain sulfation, because knockdown of mouse N-deacetylase/N-sulfotransferase, which catalyzes the first step of HS sulfation, in mESCs gave similar results to those observed in PAPST-knockdown mESCs, but depletion of CS chains did not. On the other hand, during embryoid body formation, PAPST-knockdown mESCs exhibited abnormal differentiation, in particular neurogenesis was promoted, presumably due to the observed defects in BMP, FGF and Wnt signaling. The latter were reduced as a result of the reduction in both HS and CS chain sulfation. We propose that PAPST-dependent sulfation of HS or CS chains, which is regulated developmentally, regulates the extrinsic signaling required for the maintenance and normal differentiation of mESCs. |
| doi_str_mv | 10.1371/journal.pone.0008262 |
| format | Article |
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Mutation and RNA interference (RNAi) of the Drosophila PAPST have shown the importance of PAPST-dependent sulfation of carbohydrates and proteins during development. However, the functional roles of PAPST in mammals are largely unknown. Here, we investigated whether PAPST-dependent sulfation is involved in regulating signaling pathways required for the maintenance of mouse embryonic stem cells (mESCs), differentiation into the three germ layers, and neurogenesis. By using a yeast expression system, mouse PAPST1 and PAPST2 proteins were shown to have PAPS transport activity with an apparent K(m) value of 1.54 microM or 1.49 microM, respectively. RNAi-mediated knockdown of each PAPST induced the reduction of chondroitin sulfate (CS) chain sulfation as well as heparan sulfate (HS) chain sulfation, and inhibited mESC self-renewal due to defects in several signaling pathways. However, we suggest that these effects were due to reduced HS, not CS, chain sulfation, because knockdown of mouse N-deacetylase/N-sulfotransferase, which catalyzes the first step of HS sulfation, in mESCs gave similar results to those observed in PAPST-knockdown mESCs, but depletion of CS chains did not. On the other hand, during embryoid body formation, PAPST-knockdown mESCs exhibited abnormal differentiation, in particular neurogenesis was promoted, presumably due to the observed defects in BMP, FGF and Wnt signaling. The latter were reduced as a result of the reduction in both HS and CS chain sulfation. We propose that PAPST-dependent sulfation of HS or CS chains, which is regulated developmentally, regulates the extrinsic signaling required for the maintenance and normal differentiation of mESCs.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0008262</identifier><identifier>PMID: 20011239</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Anion Transport Proteins - genetics ; Anion Transport Proteins - metabolism ; Bone morphogenetic proteins ; Carbohydrates ; Cell Biology/Cell Signaling ; Cell Biology/Extra-Cellular Matrix ; Cell Differentiation ; Cell Proliferation ; Cell self-renewal ; Chains ; Chondroitin sulfate ; Chondroitin Sulfates - metabolism ; Defects ; Developmental Biology ; Developmental Biology/Stem Cells ; Differentiation ; Down-Regulation ; Drosophila ; Embryo cells ; Embryo, Mammalian - cytology ; Embryonic stem cells ; Embryonic Stem Cells - cytology ; Embryonic Stem Cells - metabolism ; Embryos ; Gene expression ; Gene Knockdown Techniques ; Germ Layers - cytology ; Golgi apparatus ; Heparan sulfate ; Heparitin Sulfate - metabolism ; Kinases ; Kinetics ; Maintenance ; Mice ; Models, Biological ; Mutation ; N-Deacetylase ; N-deacetylase/N-sulfotransferase ; N-sulfotransferase ; Neurogenesis ; Phosphoadenosine Phosphosulfate - metabolism ; Proteins ; Reduction ; Ribonucleic acid ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA-mediated interference ; Signal Transduction ; Signaling ; Stem cell transplantation ; Stem cells ; Substrate Specificity ; Sulfates ; Sulfates - metabolism ; Sulfation ; Sulfotransferase ; Transport ; Wnt protein ; Yeast</subject><ispartof>PloS one, 2009-12, Vol.4 (12), p.e8262-e8262</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>2009 Sasaki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Sasaki et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-e8b4e4157fe0e8c1ca4a4a5881644708f1e625a904c89387b88c78347c915f393</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788424/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788424/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20011239$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sasaki, Norihiko</creatorcontrib><creatorcontrib>Hirano, Takuya</creatorcontrib><creatorcontrib>Ichimiya, Tomomi</creatorcontrib><creatorcontrib>Wakao, Masahiro</creatorcontrib><creatorcontrib>Hirano, Kazumi</creatorcontrib><creatorcontrib>Kinoshita-Toyoda, Akiko</creatorcontrib><creatorcontrib>Toyoda, Hidenao</creatorcontrib><creatorcontrib>Suda, Yasuo</creatorcontrib><creatorcontrib>Nishihara, Shoko</creatorcontrib><title>The 3'-phosphoadenosine 5'-phosphosulfate transporters, PAPST1 and 2, contribute to the maintenance and differentiation of mouse embryonic stem cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Recently, we have identified two 3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporters (PAPST1 and PAPST2), which contribute to PAPS transport into the Golgi, in both human and Drosophila. Mutation and RNA interference (RNAi) of the Drosophila PAPST have shown the importance of PAPST-dependent sulfation of carbohydrates and proteins during development. However, the functional roles of PAPST in mammals are largely unknown. Here, we investigated whether PAPST-dependent sulfation is involved in regulating signaling pathways required for the maintenance of mouse embryonic stem cells (mESCs), differentiation into the three germ layers, and neurogenesis. By using a yeast expression system, mouse PAPST1 and PAPST2 proteins were shown to have PAPS transport activity with an apparent K(m) value of 1.54 microM or 1.49 microM, respectively. RNAi-mediated knockdown of each PAPST induced the reduction of chondroitin sulfate (CS) chain sulfation as well as heparan sulfate (HS) chain sulfation, and inhibited mESC self-renewal due to defects in several signaling pathways. However, we suggest that these effects were due to reduced HS, not CS, chain sulfation, because knockdown of mouse N-deacetylase/N-sulfotransferase, which catalyzes the first step of HS sulfation, in mESCs gave similar results to those observed in PAPST-knockdown mESCs, but depletion of CS chains did not. On the other hand, during embryoid body formation, PAPST-knockdown mESCs exhibited abnormal differentiation, in particular neurogenesis was promoted, presumably due to the observed defects in BMP, FGF and Wnt signaling. The latter were reduced as a result of the reduction in both HS and CS chain sulfation. We propose that PAPST-dependent sulfation of HS or CS chains, which is regulated developmentally, regulates the extrinsic signaling required for the maintenance and normal differentiation of mESCs.</description><subject>Animals</subject><subject>Anion Transport Proteins - genetics</subject><subject>Anion Transport Proteins - metabolism</subject><subject>Bone morphogenetic proteins</subject><subject>Carbohydrates</subject><subject>Cell Biology/Cell Signaling</subject><subject>Cell Biology/Extra-Cellular Matrix</subject><subject>Cell Differentiation</subject><subject>Cell Proliferation</subject><subject>Cell self-renewal</subject><subject>Chains</subject><subject>Chondroitin sulfate</subject><subject>Chondroitin Sulfates - metabolism</subject><subject>Defects</subject><subject>Developmental Biology</subject><subject>Developmental Biology/Stem Cells</subject><subject>Differentiation</subject><subject>Down-Regulation</subject><subject>Drosophila</subject><subject>Embryo cells</subject><subject>Embryo, Mammalian - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sasaki, Norihiko</au><au>Hirano, Takuya</au><au>Ichimiya, Tomomi</au><au>Wakao, Masahiro</au><au>Hirano, Kazumi</au><au>Kinoshita-Toyoda, Akiko</au><au>Toyoda, Hidenao</au><au>Suda, Yasuo</au><au>Nishihara, Shoko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The 3'-phosphoadenosine 5'-phosphosulfate transporters, PAPST1 and 2, contribute to the maintenance and differentiation of mouse embryonic stem cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2009-12-11</date><risdate>2009</risdate><volume>4</volume><issue>12</issue><spage>e8262</spage><epage>e8262</epage><pages>e8262-e8262</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Recently, we have identified two 3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporters (PAPST1 and PAPST2), which contribute to PAPS transport into the Golgi, in both human and Drosophila. Mutation and RNA interference (RNAi) of the Drosophila PAPST have shown the importance of PAPST-dependent sulfation of carbohydrates and proteins during development. However, the functional roles of PAPST in mammals are largely unknown. Here, we investigated whether PAPST-dependent sulfation is involved in regulating signaling pathways required for the maintenance of mouse embryonic stem cells (mESCs), differentiation into the three germ layers, and neurogenesis. By using a yeast expression system, mouse PAPST1 and PAPST2 proteins were shown to have PAPS transport activity with an apparent K(m) value of 1.54 microM or 1.49 microM, respectively. RNAi-mediated knockdown of each PAPST induced the reduction of chondroitin sulfate (CS) chain sulfation as well as heparan sulfate (HS) chain sulfation, and inhibited mESC self-renewal due to defects in several signaling pathways. However, we suggest that these effects were due to reduced HS, not CS, chain sulfation, because knockdown of mouse N-deacetylase/N-sulfotransferase, which catalyzes the first step of HS sulfation, in mESCs gave similar results to those observed in PAPST-knockdown mESCs, but depletion of CS chains did not. On the other hand, during embryoid body formation, PAPST-knockdown mESCs exhibited abnormal differentiation, in particular neurogenesis was promoted, presumably due to the observed defects in BMP, FGF and Wnt signaling. The latter were reduced as a result of the reduction in both HS and CS chain sulfation. We propose that PAPST-dependent sulfation of HS or CS chains, which is regulated developmentally, regulates the extrinsic signaling required for the maintenance and normal differentiation of mESCs.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20011239</pmid><doi>10.1371/journal.pone.0008262</doi><tpages>e8262</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2009-12, Vol.4 (12), p.e8262-e8262 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1292202811 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animals Anion Transport Proteins - genetics Anion Transport Proteins - metabolism Bone morphogenetic proteins Carbohydrates Cell Biology/Cell Signaling Cell Biology/Extra-Cellular Matrix Cell Differentiation Cell Proliferation Cell self-renewal Chains Chondroitin sulfate Chondroitin Sulfates - metabolism Defects Developmental Biology Developmental Biology/Stem Cells Differentiation Down-Regulation Drosophila Embryo cells Embryo, Mammalian - cytology Embryonic stem cells Embryonic Stem Cells - cytology Embryonic Stem Cells - metabolism Embryos Gene expression Gene Knockdown Techniques Germ Layers - cytology Golgi apparatus Heparan sulfate Heparitin Sulfate - metabolism Kinases Kinetics Maintenance Mice Models, Biological Mutation N-Deacetylase N-deacetylase/N-sulfotransferase N-sulfotransferase Neurogenesis Phosphoadenosine Phosphosulfate - metabolism Proteins Reduction Ribonucleic acid RNA RNA, Messenger - genetics RNA, Messenger - metabolism RNA-mediated interference Signal Transduction Signaling Stem cell transplantation Stem cells Substrate Specificity Sulfates Sulfates - metabolism Sulfation Sulfotransferase Transport Wnt protein Yeast |
| title | The 3'-phosphoadenosine 5'-phosphosulfate transporters, PAPST1 and 2, contribute to the maintenance and differentiation of mouse embryonic stem cells |
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