3. mTOR pathway and disease Incorporates contributions from labs of Blenis, Thomas, Hafen, Cantley, Pan, White, Kwiatkowski, Hunter, Edgar, and many others. TSC/LAM
13. Vessel defects in G L/mLST8-null yolk sacs and embryos mTOR, rictor, raptor, and G L/mLST8 KOs fall into two classes, likely reflecting absence of mTORC1 or mTORC2 function
15. mTORC1 pathway activity in G L null MEFs Loss of G L/mLST8 has no apparent effect on any mTORC1 pathway assay Why?
16. G L/mLST8 is necessary for mTORC2 but not mTORC1 integrity G L: G L: G L:
17. Signaling by hemi-phosphorylated Akt mTORC2 is necessary only for signaling to FOXO Why does hemi-phosphorylated Akt signal to some effectors but not others? What does G L/mLST8 do for mTORC1?
20. Is rheb the disease-relevant effector of TSC1/2? Is mTOR the disease-relevant effector of TSC/rheb? PRO Much work in Drosophila and mammalian tissue culture What is the key evidence needed to be able to say yes with confidence? CON Other known effects of TSC2 loss. Other known targets of rheb. Incapacity of rapamycin to reverse all effects of TSC1/TSC2 loss. How can we rule out or in other potential effectors?
23. Is it best to target mTOR or a downstream effector like S6K1? No evidence either way. How can this be tested?
24. Will long-term removal by rapamycin of the inhibitory signal from S6K1 to the PI3K pathway produce unacceptable toxicities? Will TSC and LAM cells differ in above question? Will effect of long term rapamycin on mTORC2 have clinical implications?
25.
26. Anne Carpenter Jacob Chudnovsky Xana Frias David Guertin Peggy Hsu Ray Jones Nada Kalaany Tony Kang Mike Lamprecht Kathleen Ottina Funding Whitehead Institute, NIH (NIAID, NCI, GM), Keck Foundation, Pew Charitable Trust, Rita Allen Foundation The RNAi Consortium (TRC) Jason Moffat Adam Papallo Tim Peterson Jan Reiling Yasemin Sancak Dos Sarbassov Shomit Sengupta Joon-Ho Sheen Deanna Stevens Carson Thoreen