Ras signaling in aging and metabolic regulation

Abstract

Aberrant signal transduction downstream of the Ras GTPase has a well-established role in tumorigenesis. Mutations that result in hyperactivation of Ras are responsible for a third of all human cancers. Hence, small molecule inhibitors of the Ras signal transduction cascade have been under intense focus as potential cancer treatments. In both invertebrate and mammalian models, emerging evidence has also implicated components of the Ras signaling pathway in aging and metabolic regulation. Here, I review the current evidence for Ras signaling in these newly discovered roles highlighting the interactions between the Ras pathway and other longevity assurance mechanisms. Defining the role of Ras signaling in maintaining age-related health may have important implications for the development of interventions that could not only increase lifespan but also delay the onset and/or progression of age-related functional decline.

Keywords: Lifespan; Ras signaling; aging; metabolism.

Fig.1

The Ras/MAPK signaling pathway. The Ras/MAPK signaling pathway responds to extracellular cues to control cell survival, proliferation and metabolism. Growth factor binding to receptor tyrosine kinases (RTK) activates autophosphorylation of the receptor which generates binding sites for the Grb2 and Shc adaptor proteins. These adaptor proteins recruit the Ras GTPase exchange factor (GEF), SOS, to the inner surface of the membrane. SOS catalyses the exchange of GDP to GTP on Ras and then the activated Ras-GTP recruits Raf to the complex. Raf then initiates a downstream phosphorylation cascade via MEK and ERK. Activated ERK phosphorylates multiple cytoplasmic and cytoskeletal proteins including ribosomal S6 kinase (RSK). In addition, activated ERK can translocate to the nucleus, where it phosphorylates and activates members of the the E-twenty-six (ETS) transcription factor family.

Fig.2

Integration of Ras/MAPK signaling with other aging pathways. The Ras/MAPK signaling pathway is intricately connected to other cellular pathways that impact on aging. Ras signaling is activated downstream of the activated insulin receptor. Ras can directly bind to and allosterically activate PI3K. Activated ERK phosphorylates an inhibitory site on AMPK negatively regulating its activation. Phosphorylation of the TSC by ERK increases mTORC1 activity. Phosphorylation by ERK inhibits the TSC’s GAP function [76] thereby increasing mTORC1 activity. ERK also activates mTORC1 via phosphorylation of RAPTOR. ERK phosphorylation of the FOXO3A transcription factor leads to FOXO3A degradation via the ubiquitin proteasome system. Dietary restriction (DR) inhibits Ras-GTP and ERK activity, activates AMPK, inhibits mTOR and may inhibit insulin signaling via PI3K and AKT. Positive regulatory interactions are indicated by arrows. Negative regulatory interactions are shown as blunt-ended lines.