Structural fingerprints, interactions, and signaling networks of RAS family proteins beyond RAS isoforms

Abstract

Among the signaling molecules indirectly linked to many different cell surface receptors, RAS proteins essentially respond to a diverse range of extracellular cues. They control activities of multiple signaling pathways and consequently a wide array of cellular processes, including survival, growth, adhesion, migration, and differentiation. Any dysregulation of these pathway leads, thus, to cancer, developmental disorders, metabolic, and cardiovascular diseases. The biochemistry of RAS family proteins has become multifaceted since the discovery of the first members, more than 40 years ago. Substantial knowledge has been attained about molecular mechanisms underlying post-translational modification, membrane localization, regulation, and signal transduction through diverse effector molecules. However, the increasing complexity of the underlying signaling mechanisms is considerable, in part due to multiple effector pathways, crosstalks between them and eventually feedback mechanisms. Here, we take a broad view of regulatory and signaling networks of all RAS family proteins that extends beyond RAS paralogs. As described in this review, a lot is known but a lot has to be discovered yet.

Graphical abstract: The RAS paralogs, KRAS4B, NRAS, and HRAS, are the best investigated members of the RAS family, not only because of their oncogenic capacity. This protein family, however, contains 22 additional isoforms and paralogs, most of which are distantly related, with typically 20–30% amino acid identity, although they share a conserved GTP-binding domain [the color spectrum goes from white (for identical) through yellow and orange (for partially conserved) to red (for highly variable amino acids). RAS family proteins control a wide array of signaling pathways and cellular processes distinct from those controlled by RAS paralogs. This review focuses on common features and differences of RAS family proteins regarding their structure, function, regulation, signaling, and involvement in diseases.

Keywords:

• Effectors
• GAPs
• GEFs
• protein family
• RAS
• scaffold proteins
• signal transduction

Acknowledgements

We thank Dr Balal Sadeghi for critical reading of the manuscript. We are grateful to our colleagues from the Institute of Biochemistry and Molecular Biology II of the Heinrich-Heine University Düsseldorf for their support. We apologize to the many scientists and colleagues whose original studies could not be included in this Review owing to space constraints.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This study was supported by the Research committee of the Medical Faculty of the Heinrich-Heine University Düsseldorf (FoKo; grant number 9772617); the German Research Foundation (Deutsche Forschungsgemeinschaft or DFG) through the Collaborative Research Center 974 [SFB 974; project A03]; the German Federal Ministry of Education and Research (BMBF) – German Network of RASopathy Research (GeNeRARe); the European Network on Noonan Syndrome and Related Disorders (NSEuroNet).