Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity
<p>Abstract</p> <p>Background</p> <p>Retrotransposition of mRNA transcripts gives occasionally rise to functional retrogenes. Through acquiring tempero-spatial expression patterns distinct from their parental genes and/or functional mutations in their coding sequences,...
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| Format: | Article |
| Language: | English |
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BMC
2010-02-01
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| Series: | BMC Evolutionary Biology |
| Online Access: | http://www.biomedcentral.com/1471-2148/10/55 |
| _version_ | 1818907433132621824 |
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| author | Penzkofer Tobias Luz Hannes Paluch Taisa Zhang Zhongchun Duchniewicz Marlena Zemojtel Tomasz Scheele Jürgen S Zwartkruis Fried JT |
| author_facet | Penzkofer Tobias Luz Hannes Paluch Taisa Zhang Zhongchun Duchniewicz Marlena Zemojtel Tomasz Scheele Jürgen S Zwartkruis Fried JT |
| author_sort | Penzkofer Tobias |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Retrotransposition of mRNA transcripts gives occasionally rise to functional retrogenes. Through acquiring tempero-spatial expression patterns distinct from their parental genes and/or functional mutations in their coding sequences, such retrogenes may in principle reshape signalling networks.</p> <p>Results</p> <p>Here we present evidence for such a scenario, involving retrogenes of Rap1 belonging to the Ras family of small GTPases. We identified two murine and one human-specific retrogene of Rap1A and Rap1B, which encode proteins that differ by only a few amino acids from their parental Rap1 proteins. Markedly, human hRap1B-retro and mouse mRap1A-retro1 acquired mutations in the 12<sup>th </sup>and 59<sup>th </sup>amino acids, respectively, corresponding to residues mutated in constitutively active oncogenic Ras proteins. Statistical and structural analyses support a functional evolution scenario, where Rap1 isoforms of retrogenic origin are functionally distinct from their parental proteins. Indeed, all retrogene-encoded GTPases have an increased GTP/GDP binding ratio <it>in vivo</it>, indicating that their conformations resemble that of active GTP-bound Rap1. We furthermore demonstrate that these three Rap1 isoforms exhibit distinct affinities for the Ras-binding domain of RalGDS. Finally, when tested for their capacity to induce key cellular processes like integrin-mediated cell adhesion or cell spreading, marked differences are seen.</p> <p>Conclusions</p> <p>Together, these data lend strong support for an evolution scenario, where retrotransposition and subsequent mutation events generated species-specific Rap1 isoforms with differential signaling potential. Expression of the constitutively active human Rap1B-retro in cells like those derived from Ramos Burkitt's lymphoma and bone marrow from a patient with myelodysplastic syndrome (MDS) warrants further investigation into its role in disease development.</p> |
| first_indexed | 2024-12-19T21:55:02Z |
| format | Article |
| id | doaj.art-f17d78ff0b2a45b0bdca1ab3fd9dc64a |
| institution | Directory Open Access Journal |
| issn | 1471-2148 |
| language | English |
| last_indexed | 2024-12-19T21:55:02Z |
| publishDate | 2010-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Evolutionary Biology |
| spelling | doaj.art-f17d78ff0b2a45b0bdca1ab3fd9dc64a2022-12-21T20:04:18ZengBMCBMC Evolutionary Biology1471-21482010-02-011015510.1186/1471-2148-10-55Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacityPenzkofer TobiasLuz HannesPaluch TaisaZhang ZhongchunDuchniewicz MarlenaZemojtel TomaszScheele Jürgen SZwartkruis Fried JT<p>Abstract</p> <p>Background</p> <p>Retrotransposition of mRNA transcripts gives occasionally rise to functional retrogenes. Through acquiring tempero-spatial expression patterns distinct from their parental genes and/or functional mutations in their coding sequences, such retrogenes may in principle reshape signalling networks.</p> <p>Results</p> <p>Here we present evidence for such a scenario, involving retrogenes of Rap1 belonging to the Ras family of small GTPases. We identified two murine and one human-specific retrogene of Rap1A and Rap1B, which encode proteins that differ by only a few amino acids from their parental Rap1 proteins. Markedly, human hRap1B-retro and mouse mRap1A-retro1 acquired mutations in the 12<sup>th </sup>and 59<sup>th </sup>amino acids, respectively, corresponding to residues mutated in constitutively active oncogenic Ras proteins. Statistical and structural analyses support a functional evolution scenario, where Rap1 isoforms of retrogenic origin are functionally distinct from their parental proteins. Indeed, all retrogene-encoded GTPases have an increased GTP/GDP binding ratio <it>in vivo</it>, indicating that their conformations resemble that of active GTP-bound Rap1. We furthermore demonstrate that these three Rap1 isoforms exhibit distinct affinities for the Ras-binding domain of RalGDS. Finally, when tested for their capacity to induce key cellular processes like integrin-mediated cell adhesion or cell spreading, marked differences are seen.</p> <p>Conclusions</p> <p>Together, these data lend strong support for an evolution scenario, where retrotransposition and subsequent mutation events generated species-specific Rap1 isoforms with differential signaling potential. Expression of the constitutively active human Rap1B-retro in cells like those derived from Ramos Burkitt's lymphoma and bone marrow from a patient with myelodysplastic syndrome (MDS) warrants further investigation into its role in disease development.</p>http://www.biomedcentral.com/1471-2148/10/55 |
| spellingShingle | Penzkofer Tobias Luz Hannes Paluch Taisa Zhang Zhongchun Duchniewicz Marlena Zemojtel Tomasz Scheele Jürgen S Zwartkruis Fried JT Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity BMC Evolutionary Biology |
| title | Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity |
| title_full | Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity |
| title_fullStr | Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity |
| title_full_unstemmed | Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity |
| title_short | Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity |
| title_sort | retrotransposition and mutation events yield rap1 gtpases with differential signalling capacity |
| url | http://www.biomedcentral.com/1471-2148/10/55 |
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