title: Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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 12th and 59th 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 in vivo, 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany. zemojtel@molgen.mpg.de
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zemojtel
authors.forename: Marlena
authors.initials: M
authors.lastname: Duchniewicz
authors.forename: Zhongchun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Taisa
authors.initials: T
authors.lastname: Paluch
authors.forename: Hannes
authors.initials: H
authors.lastname: Luz
authors.forename: Tobias
authors.initials: T
authors.lastname: Penzkofer
authors.forename: Jürgen S
authors.initials: JS
authors.lastname: Scheele
authors.forename: Fried J T
authors.initials: FJ
authors.lastname: Zwartkruis
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D018626:Retroelements; D048348:Reverse Transcription; D020827:rap1 GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018626:Retroelements; D020827:rap1 GTP-Binding Proteins