Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity
- Equal contributors
1 Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany
2 Department of Bioinformatics, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
3 Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
4 Department of Medicine I, University of Freiburg Medical Center, D-79106 Freiburg, Germany
5 Department of Physiological Chemistry, Center for Biomedical Genetics and Cancer Genomics Centre, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
BMC Evolutionary Biology 2010, 10:55 doi:10.1186/1471-2148-10-55Published: 19 February 2010
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.
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.
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.