Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity.
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.
Zemojtel
Tomasz
T
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany. zemojtel@molgen.mpg.de
Duchniewicz
Marlena
M
Zhang
Zhongchun
Z
Paluch
Taisa
T
Luz
Hannes
H
Penzkofer
Tobias
T
Scheele
Jürgen S
JS
Zwartkruis
Fried J T
FJ
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*
D018626:Retroelements; D020827:rap1 GTP-Binding Proteins