Dataset Information

A Long-Range Recruitment Mechanism for mTORC2 Phosphorylation of Akt

ABSTRACT: Study of the phosphorylation of human Akt1 (Akt) by mTOR complex 2 (mTORC2) in vitro. Akt was prepared by semi-synthesis, resulting in a non-phosphorylated C-tail, allowing unbiased study of the sites phosphorylated by mTORC2. Because enzymologic data showed that the canonical hydrophobic motif residue, Akt Ser473, accounts for only a portion of the phosphorylation, and because the C-tail has at least 4 known phospho sites (Ser473, Ser475, Ser477, Thr479) and numerous other candidates, we sought to determine the catalog of sites on Akt that mTORC2 phosphorylates.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Brad Palanski

LAB HEAD: Philip Cole

PROVIDER: PXD048719 | Pride | 2026-02-02

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	2023-07-14-AKT-sample_10_S1-A10_1_1729.mzML	Mzml
	2023-07-14-AKT-sample_11_S1-A11_1_1730.mzML	Mzml
	2023-07-14-AKT-sample_12_S1-A12_1_1731.mzML	Mzml
	2023-07-14-AKT-sample_1_S1-A1_1_1732.mzML	Mzml
	2023-07-14-AKT-sample_2_S1-A2_1_1733.mzML	Mzml

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Publications

Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2.

Taylor Martin S MS Chen Maggie M Hancock Matthew M Wranik Maximilian M Miller Bryant D BD O'Meara Timothy R TR Palanski Brad A BA Ficarro Scott B SB Groendyke Brian J BJ Xiang Yufei Y Kondo Kazuma T KT Linde-Garelli Karen Y KY Lee Michelle J MJ Mondal Dibyendu D Freund Daniel D Congreve Samantha S Matas Kaay K Hennink Maximiliaan M Xibinaku Kera K Valenstein Max L ML van Eeuwen Trevor T Marto Jarrod A JA Sali Andrej A Shi Yi Y Gray Nathanael S NS Sabatini David M DM Chu Nam N Rogala Kacper B KB Cole Philip A PA

Science (New York, N.Y.) 20251127

The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely ...[more]

PMID: 41308123

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Project description:DallePezze2012 - TSC-independent mTORC2 regulation This model is described in the article: A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K. Sci Signal 2012 Mar; 5(217): ra25 Abstract: The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2. By analyzing the effects of perturbations targeting several levels within the network in silico and experimentally, we found that, in contrast to current hypotheses, the TSC1-TSC2 complex was not a direct or indirect (acting through the negative feedback loop) regulator of mTORC2. Although mTORC2 activation required active PI3K, this was not affected by the negative feedback loop. Therefore, we propose an mTORC2 activation pathway through a PI3K variant that is insensitive to the negative feedback loop that regulates mTORC1. This putative pathway predicts that mTORC2 would be refractory to Akt, which inhibits TSC1-TSC2, and, indeed, we found that mTORC2 was insensitive to constitutive Akt activation in several cell types. Our results suggest that a previously unknown network structure connects mTORC2 to its upstream cues and clarifies which molecular connectors contribute to mTORC2 activation. This model is hosted on BioModels Database and identified by: BIOMD0000000581. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.