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 Background: 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 Objective: To determine if RalGAPs may serve as a point of integration of the Ral and mTOR signaling networks Results: 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. Conclusion: 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. References: 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. 1374–1386