Ral and RhebGTPase Activating Proteins Integrate mTOR and

Ral and RhebGTPase 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
Molecular Cell, 53 (2014), 2:165-362
Presenter: Ye Vone Yap
Date/Time: May 1st, 2014; 15:10-16:00
Commentator: Chang-Shi, Chen,Ph.D
Location: Room 602, Med College Building
Mechanistic target of rapamycin (mTOR) signaling is one of the major signaling node that is aberrantly
activated in cancer, diabetes, and neurodegenerative disorders. mTOR is a protein kinase that forms two
complexes, mTORC1 and mTORC2, that are distinguished by their association with Raptor or Rictor,
respectively. Thus far, there are many unresolved and poorly understood issues of the signaling
mechanisms that regulate mTORC1 activity. mTORC1 activity is regulated by various extracellular
stimuli: growth factors and amino acids. Tuberous sclerosis complex (TSC), a major upstream regulator
of mTORC1 is the comprised of Tsc1/2 heterodimer that acts as a GTPase activating protein (GAP) for
the Rheb small GTPase by converting active Rheb-GTP to inactive Rheb-GDP. RalGTPases are
regulators of the octamericexocyst complex which controls vesicular transport by tethering secretory
vesicles to the plasma membrane prior to fusion. The exocyst functions independent of exocytosis and
aberrant Ral activation has been involved in cancer growth
To determine if RalGAPs may serve as a point of integration of the Ral and mTOR signaling networks
Firstly, it was identified that the RalGAP complex, acting through inhibition of RalB, as a negative
regulator of mTORC1 signaling through Sec5 and the exocyst complex. Secondly, they identified
Tsc1/2 as mTORC1-independent negative regulator of Ral. Thirdly, the loss ofC. elegans RalGAPα or
RalGAPβ orthologsphenocopied CeTORC1activation and decreased lifespan, suggesting that
in C. elegans RalGAPreplaces the Tsc complex. Finally, it was showed thatRalB activation drives
pancreatic cancer invasion and metastasis. Currently, it was illustrated that RalB-mediated mTORC1
activation is important for this activity.The observations indicated an unexpected signaling crosstalk
between the Ras-Ral and Rheb-mTOR signaling axes.
It was determined that GAPs for the Ral and Rheb small GTPases can facilitate the convergence and
interplay of two signaling networks previously considered distinct. As these components werefound to
share signaling network, combination approaches for blocking Ral or mTOR may be more effective in
clinical applications.
Neel et al.(2012)The RalB small GTPase mediates formation of invadopodia through a GTPaseactivating protein-independent function of the RalBP1/RLIP76 effector, Mol. Cell. Biol., 32 (2012), pp.