Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion. Academic Article uri icon


  • 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 RalGAP-RalGAP heterodimer shares sequence and structural similarity with Tsc1-Tsc2. Unexpectedly, we observed that C.elegans expresses orthologs for the Rheb andRalA/B GTPases and for RalGAP/, 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-likefunction. 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.

published proceedings

  • Mol Cell

altmetric score

  • 7.75

author list (cited authors)

  • Martin, T. D., Chen, X., Kaplan, R., Saltiel, A. R., Walker, C. L., Reiner, D. J., & Der, C. J.

citation count

  • 106

complete list of authors

  • Martin, Timothy D||Chen, Xiao-Wei||Kaplan, Rebecca EW||Saltiel, Alan R||Walker, Cheryl L||Reiner, David J||Der, Channing J

publication date

  • January 2014