|
Figure 2.
TSC1/2 integrates multiple signals to control cell growth and proliferation
Growth factors stimulate the MAPK and insulin signaling pathways, leading to TSC2 phosphorylation and inactivation. TSC1/2 negatively regulates mTORC1 through its actions on Rheb, while it positively regulates mTORC2. The insulin signaling pathway can activate mTORC1 without going through TSC1/2 by Akt phosphorylation of PRAS40, an inhibitor of mTORC1, thereby relieving the inhibition. Similarly, the MAPK signaling pathway can activate mTORC1 without going through TSC1/2 via RSK phosphorylation of raptor, a component of the mTORC1 complex, leading to mTORC1 activation. Activation of mTORC1 leads to protein translation and to a negative feedback loop on the activation of the insulin and MAPK signaling pathways. In the presence of amino acids, the Rag GTPase heterodimers promote the localization of mTORC1 to cellular compartments containing Rheb, thereby promoting mTORC1 activation. In conditions of low cellular energy or hypoxia, AMPK phosphorylates and activates TSC2, while hypoxia increases the transcription of REDD1, which also activates TSC2, leading to inhibition of translation. TSC2 binds p27Kip1, a cyclin-dependent kinase inhibitor, stabilizing it and resulting in inhibition of cell cycle progression. Sirolimus, or rapamycin, inhibits mTORC1, while CI-1040 is an MAPK/ERK inhibitor. Roscovitine is an inhibitor of CDK2. 4E-BP1, factor 4E-binding protein 1; Akt, protein kinase B; AMPK, AMP-dependent protein kinase; CDK2, cyclin-dependent kinase 2; ERK1/2, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; mTORC, mammalian target of rapamycin complex; PDK1, pyruvate dehydrogenase kinase, isozyme 1; PI3K, phosphoinositide 3-kinase; PRAS40, proline-rich protein kinase B substrate of 40 kDa; Rag, Ras-related small GTP-binding protein; REDD1, regulated in the development and DNA damage response 1; Rheb, Ras homolog enriched in brain; RSK, p90 ribosomal S6 kinase; S6K1, S6 kinase 1; TSC, tuberous sclerosis complex. |
