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. 2014 Dec 1;6:116. doi: 10.12703/P6-116

Figure 2. Simplified diagram of the mammalian target of rapamycin (mTOR) signaling pathway and its relationship with autophagy and apoptosis.

Figure 2.

Tuberous sclerosis complex (TSC)1/2 integrates multiple signals to control cell size and proliferation. TSC1/2 regulates mammalian target of rapamycin (mTOR) complex 1 mTORC1 negatively through its actions on Rheb. Activation of mTORC1 leads to protein translation, cell growth and proliferation. mTORC1 is a major regulator of autophagy. Blockade of mTORC1 by sirolimus augments autophagy, leading to increased cell survival. This effect can be inhibited by hydroxychloroquine. mTOR complex 2 (mTORC2) regulates the actin cytoskeleton through Rho GTPases, which affect cell migration, morphogenesis and apoptosis. Simvastatin reduces Rheb and Rho activities and promotes apoptosis. Combined therapy with sirolimus, hydroxychloroquine or simvastatin may act synergically to inhibit lymphangioleiomyomatosis (LAM) cell growth and promote apoptosis.

Abbreviations: Akt, protein kinase B; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; Rac, small GTPase binding protein of the Rho family; Rheb, Ras homolog enriched in brain; S6K1, S6 kinase 1; 4E-BP1, factor 4E binding protein 1; TSC, tuberous sclerosis complex.