mTORC1 signaling and its effects on reproduction and longevity. Many mTOR signaling components have been shown to affect reproductive function (green asterisks) and/or lifespan (orange asterisks) in C. elegans, D. melanogaster, and/or mice; these signaling components are indicated by asterisks in this simplified mTOR schematic. The serine/threonine kinase mTOR is the catalytic subunit of two distinct complexes, mTORC1 (which includes the constituent protein Raptor, among others) and mTORC2 (which includes the constituent protein Rictor, among others). The kinase activity of mTORC1 is strongly stimulated by the GTP-bound form of Rheb (Ras homologue enriched in brain); mTORC1 is thereby negatively regulated by TSC1/TSC2 complex, which converts Rheb to its inactive GDP-bound state. mTORC1 activity can be directly regulated (i.e., by AMPK or Akt phosphorylating constituent proteins of the complex or by rapamycin acutely inhibiting mTORC1 activity), but upstream signals also indirectly control mTORC1 activity through the TSC1/2 repressor. For instance, effector kinases of the PI3K/Akt and Ras/MAPK branches of IIS (Akt or ERK1/2 and RSK, respectively) inactivate the TSC1/2 complex. In contrast, phosphorylation by AMPK increases GTPase-activating protein activity of TSC2 toward Rheb, leading to inhibition of mTORC1 activity. Other upstream regulators (not depicted) also control mTORC1 activity. mTORC1 phosphorylates many substrates, including S6K.