Ral and Rheb GTPase Activating Proteins Integrate mTOR and GTPase Signaling in Aging, Autophagy, and Tumor Cell Invasion

• Published in: Molecular cell Vol. 53; no. 2; pp. 209 - 220
• Main Authors: Martin, Timothy D., Chen, Xiao-Wei, Kaplan, Rebecca E.W., Saltiel, Alan R., Walker, Cheryl L., Reiner, David J., Der, Channing J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.01.2014
• Subjects: Animals; Autophagy - genetics; Caenorhabditis elegans - cytology; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Caenorhabditis elegans Proteins - physiology; Cell Line, Tumor; Cell Membrane - metabolism; Cellular Senescence - genetics; GTP Phosphohydrolases - metabolism; HEK293 Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Monomeric GTP-Binding Proteins - genetics; Monomeric GTP-Binding Proteins - metabolism; Monomeric GTP-Binding Proteins - physiology; Multiprotein Complexes - metabolism; Neoplasm Invasiveness - genetics; ral GTP-Binding Proteins - genetics; ral GTP-Binding Proteins - metabolism; ral GTP-Binding Proteins - physiology; Ras Homolog Enriched in Brain Protein; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Proteins - genetics
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.12.004

Diverse environmental cues converge on and are integrated by the mTOR signaling network to control cellular growth and homeostasis. The mammalian Tsc1-Tsc2 GTPase activating protein (GAP) heterodimer is a critical negative regulator of Rheb and mTOR activation. The RalGAPα-RalGAPβ heterodimer shares sequence and structural similarity with Tsc1-Tsc2. Unexpectedly, we observed that C. elegans expresses orthologs for the Rheb and RalA/B GTPases and for RalGAPα/β, but not Tsc1/2. This prompted our investigation to determine whether RalGAPs additionally modulate mTOR signaling. We determined that C. elegans RalGAP loss decreased lifespan, consistent with a Tsc-like function. Additionally, RalGAP suppression in mammalian cells caused RalB-selective activation and Sec5- and exocyst-dependent engagement of mTORC1 and suppression of autophagy. Unexpectedly, we also found that Tsc1-Tsc2 loss activated RalA/B independently of Rheb-mTOR signaling. Finally, RalGAP suppression caused mTORC1-dependent pancreatic tumor cell invasion. Our findings identify an unexpected crosstalk and integration of the Ral and mTOR signaling networks. [Display omitted] •C. elegans lifespan is controlled by hgap (RalGAP)-Ral-1-CeTOR signaling•RalGAPs negatively regulate mTORC1 signaling by controlling RalB activity•RalB forms a complex with mTORC1 that is dependent on Sec5 and the exocyst•mTOR inhibition blocks RalB-driven pancreatic tumor cell invasion