Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion

Mol Cell. 2014 Jan 23;53(2):209-20. doi: 10.1016/j.molcel.2013.12.004. Epub 2014 Jan 2.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*
  • Ras Homolog Enriched in Brain Protein
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • ral GTP-Binding Proteins / genetics
  • ral GTP-Binding Proteins / metabolism
  • ral GTP-Binding Proteins / physiology*

Substances

  • Caenorhabditis elegans Proteins
  • Multiprotein Complexes
  • RHEB-1 protein, C elegans
  • Ras Homolog Enriched in Brain Protein
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • GTP Phosphohydrolases
  • Monomeric GTP-Binding Proteins
  • ral GTP-Binding Proteins