A complex interplay between Akt, TSC2, and the two mTOR complexes

By Jingxiang Huang, B. Manning. Biochemical Society Transactions, 2009

767 citations recorded by the source corpus.

Akt/PKB both regulates and is regulated by the TSC1-TSC2 complex. Downstream of phosphoinositide 3-kinase (PI3K), Akt directly phosphorylates TSC2 on multiple sites. While the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1-TSC2 complex on Rheb and mTOR complex 1 (mTORC1), thereby activating mTORC1 in response to growth factors. Through negative feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularly evident in cells and tumors lacking the TSC1-TSC2 complex, where Akt signalling is severely attenuated due, at least in part, to constitutive activation of mTORC1. An additional level of complexity in the relationship between Akt and the TSC1-TSC2 complex has recently been uncovered. The growth factor-stimulated kinase activity of mTOR complex 2 (mTORC2 or the mTOR-Rictor complex), which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser473), was found to be defective in cells lacking the TSC1-TSC2 complex. This effect on mTORC2 can be separated from the inhibitory effects of the TSC1-TSC2 complex on Rheb and mTORC1. This review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1-TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/fd10dbb904e114bad413b9a888d7beef5eb2b9fb

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. J. Asara
2. Lewis C. Cantley
3. B. Manning
4. Alec C. Kimmelman
5. G. Hotamışlıgil

In Molecular Biology

1. B. Manning
2. Lewis C. Cantley
3. David M. Sabatini
4. J. Asara
5. Alec C. Kimmelman
6. Mark A. Rubin
7. Olivier Elemento
8. N. Divecha

In Physiology

1. B. Manning
2. Lewis C. Cantley
3. J. Asara
4. Alec C. Kimmelman
5. G. Hotamışlıgil
6. David M. Sabatini
7. Haiming Cao
8. R. Medzhitov

Citations in the corpus

• Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks (2011, background): “Since TSC2 serves as a GTPase-activating protein (GAP) and inactivates the small GTPase Rheb, its inhibition subsequently allows Rheb to directly activate mTORC1 (41, 71, 72, 119).”
• Phosphatidylinositol-5-phosphate 4-kinases regulate cellular lipid metabolism by facilitating autophagy (2018, background): “TSC2 is a negative regulator of mTORC1 activity and siRNA knockdown of TSC2 increases downstream activation of mTORC1 targets (Huang and Manning, 2008, 2009).”
• Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways (2011, background): “The primary mechanism by which Akt activates mTORC1 is through the phosphorylation and inhibition of the TSC2 protein within the TSC1-TSC2 complex (reviewed in Huang and Manning, 2009).”