Rheb may complex with RASSF1A to coordinate Hippo and TOR signaling

Abstract

The TOR pathway is a vital component of cellular homeostasis that controls the synthesis of proteins, nucleic acids and lipids. Its core is the TOR kinase. Activation of the TOR pathway suppresses autophagy, which plays a vital but complex role in tumorigenesis. The TOR pathway is regulated by activation of the Ras-related protein Rheb, which can bind mTOR. The Hippo pathway is a major growth control module that regulates cell growth, differentiation and apoptosis. Its core consists of an MST/LATS kinase cascade that can be activated by the RASSF1A tumor suppressor. The TOR and Hippo pathways may be coordinately regulated to promote cellular homeostasis. However, the links between the pathways remain only partially understood. We now demonstrate that in addition to mTOR regulation, Rheb also impacts the Hippo pathway by forming a complex with RASSF1A. Using stable clones of two human lung tumor cell lines (NCI-H1792 and NCI-H1299) with shRNA-mediated silencing or ectopic overexpression of RASSF1A, we show that activated Rheb stimulates the Hippo pathway, but is suppressed in its ability to stimulate the TOR pathway. Moreover, by selectively labeling autophagic vacuoles we show that RASSF1A inhibits the ability of Rheb to suppress autophagy and enhance cell growth. Thus, we identify a new connection that impacts coordination of Hippo and TOR signaling. As RASSF1A expression is frequently lost in human tumors, the RASSF1A status of a tumor may impact not just its Hippo pathway status, but also its TOR pathway status.

RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis—an updated review

“…RASSF1A also modulates the activity of RhoB GTPase, which functions as RhoA/RhoC antagonists 72 , through fine-tuning GEF-H1 activity by inducing its phosphorylation via NDR2 kinase 56,73 . More recently, Rheb, a Ras-related small GTPase, was shown to form a complex with RASSF1A to coordinate Hippo and TOR signaling 74 . Ultimately, the opposing function of RASSF1A seems to play a critical and cooperative role in determining the fate of the Ras GTPases family signaling as a proto-oncogene during carcinogenesis 64,75 .…”

Phosphorylated mTOR and YAP serve as prognostic markers and therapeutic targets in gliomas

“…37,38 Recent reports have provided evidence of links between the mTOR and Hippo/YAP pathways, and the crosstalk of the two pathways regulates tissue homeostasis 10,39 and tumorigenesis. 11,40 Previous studies have linked mTOR and Hippo/YAP. 41,42 Specifically, mTORC1 engages in crosstalk with YAP through various mechanisms: YAP mediates crosstalk between the Hippo and PI3K-mTOR pathways by suppressing PTEN via miR-29 10 and YAP/TAZ enhances mTORC1 activity via increase of amino-acid uptake.…”

A comprehensive analysis of RAS-effector interactions reveals interaction hotspots and new binding partners

“…3 and S4). It has been proposed that RHEB may complex with RASSF1 to coordinate signaling pathways, after processing by MST/LATS and TOR kinases (56). In the presence of RASSF1, RHEB has been shown to stimulate the MST/LATS/YAP pathways but is suppressed in its ability to activate the TOR pathway.…”