title: Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion.
abstract: 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.
authors.affiliation: University of North Carolina at Chapel Hill, Department of Pharmacology, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Martin
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.affiliation: University of North Carolina at Chapel Hill, Department of Pharmacology, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, USA.
authors.forename: Rebecca E W
authors.initials: RE
authors.lastname: Kaplan
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Walker
authors.affiliation: University of North Carolina at Chapel Hill, Department of Pharmacology, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, USA. Electronic address: dreiner@ibt.tamhsc.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Reiner
authors.affiliation: University of North Carolina at Chapel Hill, Department of Pharmacology, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, USA. Electronic address: cjder@med.unc.edu.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D046912:Multiprotein Complexes; C539143:RHEB-1 protein, C elegans; D000076205:Ras Homolog Enriched in Brain Protein; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020558:GTP Phosphohydrolases; D020559:Monomeric GTP-Binding Proteins; D020725:ral GTP-Binding Proteins