Sprouty4 is an endogenous negative modulator of TrkA signaling and neuronal differentiation induced by NGF
The Sprouty (Spry) family of proteins represents endogenous regulators of downstream signaling pathways induced by receptor tyrosine kinases (RTKs). Using real time PCR, we detect a significant increase in the expression of Spry4 mRNA in response to NGF, indicating that Spry4 could modulate intracel...
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| Veröffentlicht in: | PloS one 2012-02, Vol.7 (2), p.e32087-e32087 |
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| creator | Alsina, Fernando C Irala, Dolores Fontanet, Paula A Hita, Francisco J Ledda, Fernanda Paratcha, Gustavo |
| description | The Sprouty (Spry) family of proteins represents endogenous regulators of downstream signaling pathways induced by receptor tyrosine kinases (RTKs). Using real time PCR, we detect a significant increase in the expression of Spry4 mRNA in response to NGF, indicating that Spry4 could modulate intracellular signaling pathways and biological processes induced by NGF and its receptor TrkA. In this work, we demonstrate that overexpression of wild-type Spry4 causes a significant reduction in MAPK and Rac1 activation and neurite outgrowth induced by NGF. At molecular level, our findings indicate that ectopic expression of a mutated form of Spry4 (Y53A), in which a conserved tyrosine residue was replaced, fail to block both TrkA-mediated Erk/MAPK activation and neurite outgrowth induced by NGF, suggesting that an intact tyrosine 53 site is required for the inhibitory effect of Spry4 on NGF signaling. Downregulation of Spry4 using small interference RNA knockdown experiments potentiates PC12 cell differentiation and MAPK activation in response to NGF. Together, these findings establish a new physiological mechanism through which Spry4 regulates neurite outgrowth reducing not only the MAPK pathway but also restricting Rac1 activation in response to NGF. |
| doi_str_mv | 10.1371/journal.pone.0032087 |
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Using real time PCR, we detect a significant increase in the expression of Spry4 mRNA in response to NGF, indicating that Spry4 could modulate intracellular signaling pathways and biological processes induced by NGF and its receptor TrkA. In this work, we demonstrate that overexpression of wild-type Spry4 causes a significant reduction in MAPK and Rac1 activation and neurite outgrowth induced by NGF. At molecular level, our findings indicate that ectopic expression of a mutated form of Spry4 (Y53A), in which a conserved tyrosine residue was replaced, fail to block both TrkA-mediated Erk/MAPK activation and neurite outgrowth induced by NGF, suggesting that an intact tyrosine 53 site is required for the inhibitory effect of Spry4 on NGF signaling. Downregulation of Spry4 using small interference RNA knockdown experiments potentiates PC12 cell differentiation and MAPK activation in response to NGF. Together, these findings establish a new physiological mechanism through which Spry4 regulates neurite outgrowth reducing not only the MAPK pathway but also restricting Rac1 activation in response to NGF.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0032087</identifier><identifier>PMID: 22384148</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Axonogenesis ; Biological activity ; Biology ; Cell activation ; Cell cycle ; Cell differentiation ; Cell Line, Tumor ; Cellular biology ; Collaboration ; COS Cells ; Differentiation (biology) ; Drosophila ; Ectopic expression ; Epidermal growth factor ; Extracellular signal-regulated kinase ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Gene expression ; Genotype & phenotype ; Insects ; Intracellular signalling ; Kinases ; Laboratories ; MAP kinase ; MAP Kinase Signaling System ; Medicine ; mRNA ; Mutation ; Nerve growth factor ; Nerve Growth Factor - metabolism ; Nerve Tissue Proteins - metabolism ; Nervous system ; Neurons ; Neurons - metabolism ; Neurophysiology ; Neurosciences ; Pathways ; PC12 Cells ; Pheochromocytoma cells ; Physiological aspects ; Physiology ; Proteins ; Quantitative analysis ; rac1 GTP-Binding Protein - metabolism ; Rac1 protein ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction - methods ; Receptor, trkA - metabolism ; Regulators ; Ribonucleic acid ; RNA ; RNA, Small Interfering - metabolism ; RNA-mediated interference ; Rodents ; Signal Transduction ; siRNA ; TrkA protein ; TrkA receptors ; Tyrosine ; Tyrosine - chemistry</subject><ispartof>PloS one, 2012-02, Vol.7 (2), p.e32087-e32087</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Alsina et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (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>Alsina et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-7c6cdf8999322bb00ef261619296880efc70081f2962ebf8a4d8a841c209496f3</citedby><cites>FETCH-LOGICAL-c691t-7c6cdf8999322bb00ef261619296880efc70081f2962ebf8a4d8a841c209496f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285629/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285629/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22384148$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kahle, Philipp J.</contributor><creatorcontrib>Alsina, Fernando C</creatorcontrib><creatorcontrib>Irala, Dolores</creatorcontrib><creatorcontrib>Fontanet, Paula A</creatorcontrib><creatorcontrib>Hita, Francisco J</creatorcontrib><creatorcontrib>Ledda, Fernanda</creatorcontrib><creatorcontrib>Paratcha, Gustavo</creatorcontrib><title>Sprouty4 is an endogenous negative modulator of TrkA signaling and neuronal differentiation induced by NGF</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The Sprouty (Spry) family of proteins represents endogenous regulators of downstream signaling pathways induced by receptor tyrosine kinases (RTKs). Using real time PCR, we detect a significant increase in the expression of Spry4 mRNA in response to NGF, indicating that Spry4 could modulate intracellular signaling pathways and biological processes induced by NGF and its receptor TrkA. In this work, we demonstrate that overexpression of wild-type Spry4 causes a significant reduction in MAPK and Rac1 activation and neurite outgrowth induced by NGF. At molecular level, our findings indicate that ectopic expression of a mutated form of Spry4 (Y53A), in which a conserved tyrosine residue was replaced, fail to block both TrkA-mediated Erk/MAPK activation and neurite outgrowth induced by NGF, suggesting that an intact tyrosine 53 site is required for the inhibitory effect of Spry4 on NGF signaling. Downregulation of Spry4 using small interference RNA knockdown experiments potentiates PC12 cell differentiation and MAPK activation in response to NGF. Together, these findings establish a new physiological mechanism through which Spry4 regulates neurite outgrowth reducing not only the MAPK pathway but also restricting Rac1 activation in response to NGF.</description><subject>Animals</subject><subject>Axonogenesis</subject><subject>Biological activity</subject><subject>Biology</subject><subject>Cell activation</subject><subject>Cell cycle</subject><subject>Cell differentiation</subject><subject>Cell Line, Tumor</subject><subject>Cellular biology</subject><subject>Collaboration</subject><subject>COS Cells</subject><subject>Differentiation (biology)</subject><subject>Drosophila</subject><subject>Ectopic expression</subject><subject>Epidermal growth factor</subject><subject>Extracellular signal-regulated kinase</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Gene expression</subject><subject>Genotype & phenotype</subject><subject>Insects</subject><subject>Intracellular signalling</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System</subject><subject>Medicine</subject><subject>mRNA</subject><subject>Mutation</subject><subject>Nerve growth factor</subject><subject>Nerve Growth Factor - 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metabolism</topic><topic>Gene expression</topic><topic>Genotype & phenotype</topic><topic>Insects</topic><topic>Intracellular signalling</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System</topic><topic>Medicine</topic><topic>mRNA</topic><topic>Mutation</topic><topic>Nerve growth factor</topic><topic>Nerve Growth Factor - metabolism</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Nervous system</topic><topic>Neurons</topic><topic>Neurons - metabolism</topic><topic>Neurophysiology</topic><topic>Neurosciences</topic><topic>Pathways</topic><topic>PC12 Cells</topic><topic>Pheochromocytoma cells</topic><topic>Physiological aspects</topic><topic>Physiology</topic><topic>Proteins</topic><topic>Quantitative analysis</topic><topic>rac1 GTP-Binding Protein - metabolism</topic><topic>Rac1 protein</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Real-Time Polymerase Chain Reaction - methods</topic><topic>Receptor, trkA - 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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>Alsina, Fernando C</au><au>Irala, Dolores</au><au>Fontanet, Paula A</au><au>Hita, Francisco J</au><au>Ledda, Fernanda</au><au>Paratcha, Gustavo</au><au>Kahle, Philipp J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sprouty4 is an endogenous negative modulator of TrkA signaling and neuronal differentiation induced by NGF</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-02-23</date><risdate>2012</risdate><volume>7</volume><issue>2</issue><spage>e32087</spage><epage>e32087</epage><pages>e32087-e32087</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The Sprouty (Spry) family of proteins represents endogenous regulators of downstream signaling pathways induced by receptor tyrosine kinases (RTKs). Using real time PCR, we detect a significant increase in the expression of Spry4 mRNA in response to NGF, indicating that Spry4 could modulate intracellular signaling pathways and biological processes induced by NGF and its receptor TrkA. In this work, we demonstrate that overexpression of wild-type Spry4 causes a significant reduction in MAPK and Rac1 activation and neurite outgrowth induced by NGF. At molecular level, our findings indicate that ectopic expression of a mutated form of Spry4 (Y53A), in which a conserved tyrosine residue was replaced, fail to block both TrkA-mediated Erk/MAPK activation and neurite outgrowth induced by NGF, suggesting that an intact tyrosine 53 site is required for the inhibitory effect of Spry4 on NGF signaling. Downregulation of Spry4 using small interference RNA knockdown experiments potentiates PC12 cell differentiation and MAPK activation in response to NGF. Together, these findings establish a new physiological mechanism through which Spry4 regulates neurite outgrowth reducing not only the MAPK pathway but also restricting Rac1 activation in response to NGF.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22384148</pmid><doi>10.1371/journal.pone.0032087</doi><tpages>e32087</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Axonogenesis Biological activity Biology Cell activation Cell cycle Cell differentiation Cell Line, Tumor Cellular biology Collaboration COS Cells Differentiation (biology) Drosophila Ectopic expression Epidermal growth factor Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - metabolism Gene expression Genotype & phenotype Insects Intracellular signalling Kinases Laboratories MAP kinase MAP Kinase Signaling System Medicine mRNA Mutation Nerve growth factor Nerve Growth Factor - metabolism Nerve Tissue Proteins - metabolism Nervous system Neurons Neurons - metabolism Neurophysiology Neurosciences Pathways PC12 Cells Pheochromocytoma cells Physiological aspects Physiology Proteins Quantitative analysis rac1 GTP-Binding Protein - metabolism Rac1 protein Rats Rats, Sprague-Dawley Real-Time Polymerase Chain Reaction - methods Receptor, trkA - metabolism Regulators Ribonucleic acid RNA RNA, Small Interfering - metabolism RNA-mediated interference Rodents Signal Transduction siRNA TrkA protein TrkA receptors Tyrosine Tyrosine - chemistry |
| title | Sprouty4 is an endogenous negative modulator of TrkA signaling and neuronal differentiation induced by NGF |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T13%3A15%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Sprouty4%20is%20an%20endogenous%20negative%20modulator%20of%20TrkA%20signaling%20and%20neuronal%20differentiation%20induced%20by%20NGF&rft.jtitle=PloS%20one&rft.au=Alsina,%20Fernando%20C&rft.date=2012-02-23&rft.volume=7&rft.issue=2&rft.spage=e32087&rft.epage=e32087&rft.pages=e32087-e32087&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0032087&rft_dat=%3Cgale_plos_%3EA477051520%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1323859552&rft_id=info:pmid/22384148&rft_galeid=A477051520&rft_doaj_id=oai_doaj_org_article_26f08dc99e1e46218f686c5a1c274ebe&rfr_iscdi=true |