Ras and Rheb Signaling in Survival and Cell Death

Abstract

One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.

RASSF5 inhibits growth and invasion and induces apoptosis in osteosarcoma cells through activation of MST1/LATS1 signaling

“…RASSF binds to MST1, regulates mammalian cell proliferation (28), and triggers cell apoptosis via activation of mammalian MST1 (29). However, a few studies have demonstrated that MST1 exhibits a growth promoting activity in HCC cells (30), and LASSF5 suppresses the growth of lung cancer cells independent of MST1/2 kinase (31).…”

The small GTPases Ras and Rheb studied by multidimensional NMR spectroscopy: structure and function

“…Rheb (Ras homologue enriched in brain) is a small GTPase that is related to Ras, Rap, and Ral (Tee et al, 2003(Tee et al, , 2005Ehrkamp et al, 2013). Rheb, is part of the mTOR pathway that integrates intra-and extracellular signals and thereby regulates cell metabolism and growth proliferation.…”

Rheb may complex with RASSF1A to coordinate Hippo and TOR signaling

“…However, it can also induce apoptosis [11, 12]. This suggests that the action of Rheb in a cell may be context dependent [13]. …”

“…This interaction serves to suppress apoptosis by releasing the anti-apoptotic proteins Bcl2 and Bcl-XL from an inactive complex. Therefore, much like its cousin Ras, Rheb appears to act by binding and activating multiple effector proteins to establish a complex signaling network [13]. …”