User:Mxt15/sandbox/mTORC1

MAPK/ERK pathway[edit]
Mitogens, such as insulin like growth factor 1 (IGF1), can activate the MAPK/ERK pathway, which can inhibit the TSC1/TSC2 complex, activating mTORC1. In this pathway, the G protein Ras is tethered to the plasma membrane via a farnesyl group and is in its inactive GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein GRB2 binds with its SH2 domains. This recruits the GEF called Sos, which activates the Ras G protein. Ras activates Raf (MAPKKK), which activates Mek (MAPKK), which activates Erk (MAPK). Erk can go on to activate RSK. Erk will phosphorylate the serine residue 644 on TSC2, while RSK will phosphorylate serine residue 1798 on TSC2. These phosphorylations will cause the heterodimer to fall apart, and prevent it from deactivating Rheb, which keeps mTORC1 active.

RSK has also been shown to phosphorylate raptor, which helps it overcome the inhibitory effects of PRAS40.

JNK pathway

The c-Jun N-terminal kinase (JNK) signaling pathway is part of the mitogen-activated protein kinase (MAPK) signaling pathway essential in stress signaling pathways relating to gene expression, neuronal development, and cell survival. Studies have shown there is a direct molecular interaction where JNK phosphorylates Raptor at Ser-696, Thr-706, and Ser-863. Therefore, mTORC1 activity is JNK-dependent. Thus, JNK activation plays a role in protein synthesis via subsequent downstream effectors of mTORC1 such as S6 kinase and eIFs.

Wnt pathway[edit]
The Wnt pathway is responsible for cellular growth and proliferation during organismal development; thus, it could be reasoned that activation of this pathway also activates mTORC1. Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta (GSK3B). When the Wnt pathway is not active, GSK3 beta is able to phosphorylate TSC2 on two serine residues of 1341 and 1337 in conjunction with AMPK phosphorylating serine residue 1345. It has been found that the AMPK is required to first phosphorylate residue 1345 before GSK3 beta can phosphorylate its target serine residues. This phosphorylation of TSC2 would activate this complex, if GSK3 beta were active. Since the Wnt pathway inhibits GSK3 signaling, the active Wnt pathway is also involved in the mTORC1 pathway. Thus, mTORC1 can activate protein synthesis for the developing organism.

Cytokines[edit]
Cytokines like tumor necrosis factor alpha (TNF-alpha) can induce mTOR activity through IKK beta, also known as IKK2. IKK beta can phosphorylate TSC1 at serine residue 487 and TSC1 at serine residue 511. This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP-bound state.