Exploring the interactions of the RAS family in the human protein network and their potential implications in RAS-directed therapies

// Anibal Bueno 1 , Ian Morilla 2 , Diego Diez 3 , Aurelio A. Moya-Garcia 4 , José Lozano 1, 5 , Juan A.G. Ranea 1, 5, 6 1 Departmento de Biología Molecular y Bioquímica, Universidad de Málaga, Málaga 29071, Spain 2 Institute of Molecular Life Sciences, University of Zurich, Zurich CH-8057, Switzerland 3 Quantitative Immunology Research Unit, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan 4 Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK 5 Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain 6 CIBER de Enfermedades Raras, Madrid 28029, Spain Correspondence to: Juan A.G. Ranea, email: ranea@uma.es Keywords: Ras, network, cancer, signaling, therapy Received: May 12, 2016      Accepted: September 15, 2016      Published: October 03, 2016 ABSTRACT RAS proteins are the founding members of the RAS superfamily of GTPases. They are involved in key signaling pathways regulating essential cellular functions such as cell growth and differentiation. As a result, their deregulation by inactivating mutations often results in aberrant cell proliferation and cancer. With the exception of the relatively well-known KRAS, HRAS and NRAS proteins, little is known about how the interactions of the other RAS human paralogs affect cancer evolution and response to treatment. In this study we performed a comprehensive analysis of the relationship between the phylogeny of RAS proteins and their location in the protein interaction network. This analysis was integrated with the structural analysis of conserved positions in available 3D structures of RAS complexes. Our results show that many RAS proteins with divergent sequences are found close together in the human interactome. We found specific conserved amino acid positions in this group that map to the binding sites of RAS with many of their signaling effectors, suggesting that these pairs could share interacting partners. These results underscore the potential relevance of cross-talking in the RAS signaling network, which should be taken into account when considering the inhibitory activity of drugs targeting specific RAS oncoproteins. This study broadens our understanding of the human RAS signaling network and stresses the importance of considering its potential cross-talk in future therapies.