Ras signaling through RASSF proteins

Abstract

There are six core RASSF family proteins that contain conserved Ras Association domains and may serve as Ras effectors. They lack intrinsic enzymatic activity and appear to function as scaffolding and localization molecules. While initially being associated with pro-apoptotic signaling pathways such as Bax and Hippo, it is now clear that they can also connect Ras to a surprisingly broad range of signaling pathways that control senescence, inflammation, autophagy, DNA repair, ubiquitination and protein acetylation. Moreover, they may be able to impact the activation status of pro-mitogenic Ras effector pathways, such as the Raf pathway. The frequent epigenetic inactivation of RASSF genes in human tumors disconnects Ras from pro-death signaling systems, enhancing Ras driven transformation and metastasis. The best characterized members are RASSF1A and RASSF5 (NORE1A).

Keywords: Apoptosis; NORE1A; RASSF1A; Ras; Signaling; p53.

Fig. 1. RASSF1A modulates mitogenic Ras signaling

RASSF1A has a complex role in regulating Ras signaling through Raf-1 and AKT, primarily through its interactions with the MST2 and Src kinases and the PP1A phosphatase. Activation of Raf/MAPK signaling therefore consists of multiple feedback/control loops and should be thought of more as a complex network rather than a linear pathway. The presence/absence of RASSF1A together with cell context will likely govern the output signals from Ras signaling through this pathway.

Fig. 2. Summary of the major biological processes modulated by RASSF1A and NORE1A

RASSF1A and NORE1A interact with numerous partners to enable them to regulate diverse biological processes, including apoptosis, senescence, cell migration and protein stability. RASSF1A appears to be more apoptotic while NORE1A is a key Ras senescence effector. Although RASSF1A and NORE1A have unique functions, they may also co-ordinately regulate some of the same biological processes, such as modulating the stability of p53 by interacting with and regulating MDM2 and controlling Wnt signaling by modulating β-TrCP activity.