A possible role for long non-coding RNA in modulating signaling pathways.

Signaling proteins often engage in multiple protein-protein interactions that are dependent upon cellular context. Little is known about how signaling proteins select their interacting targets. The Ras GTPase is an example of a protein that can activate a large number of distinct and interconnected downstream signaling pathways. Hyperactive forms of Ras are commonly found in a variety of different cancers, often due to somatic mutations within the RAS gene. Despite extensive studies to identify Ras-regulated pathways, it is still not known exactly which pathways might be activated by hyperactive Ras in a given cellular and disease context. Long non-coding RNAs (lncRNAs) are RNA transcripts longer than 200 bp exhibiting spatially and temporally-regulated expression patterns. LncRNAs have been shown to harbor biological activities but the functions of the great majority of lncRNAs are not known. We hypothesize that long non-coding RNAs serve as signaling modulators linking Ras and potentially other signaling proteins to their specific downstream targets and may therefore play a key role in how signals are propagated in a specific cellular environment. In support of our hypothesis we argue that lncRNAs have been shown to bind and regulate protein complexes targeting their enzymatic activity towards specific substrates. It has also been demonstrated that specific lncRNAs are expressed in particular types of cancers where they may influence tumor progression. Studies suggest that lncRNAs have evolved to help regulate complex biological processes that require the ability to stringently discriminate between a large number of potential effectors. If our hypothesis is correct, we envision that it will be possible to predict the target pathway of a mutant protein based on the lncRNA profile in a specific cancer. More generally, this will expand our understanding of how signal transduction networks are wired within a given biological context.