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

Timothy D Martin; Xiao-Wei Chen; Rebecca E W Kaplan; Alan R Saltiel; Cheryl L Walker; David J Reiner; Channing J Der

doi:10.1016/j.molcel.2013.12.004

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.

Authors

Timothy D Martin¹, Xiao-Wei Chen², Rebecca E W Kaplan¹, Alan R Saltiel², Cheryl L Walker³, David J Reiner⁴, Channing J Der⁵

Affiliations

¹ University of North Carolina at Chapel Hill, Department of Pharmacology, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, USA.
² Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
³ Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA.
⁴ 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.
⁵ 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.

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
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
GTP Phosphohydrolases
Monomeric GTP-Binding Proteins
ral GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding