The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling

By Peggy P. Hsu, S. A. Kang, Jonathan Rameseder, Yi Zhang, K. Ottina, D. Lim, Timothy R. Peterson, Yongmun Choi, Nathanael S. Gray, Michael B. Yaffe and 2 more. Science, 2011

1,097 citations recorded by the source corpus.

A search for substrates of a growth-promoting kinase revealed a regulatory feedback loop involved in tumor suppression. The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f30fd1314566afdd115487d819a59b81fc304c77

How researchers see this paper

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

In Molecular Biology

Citations in the corpus

mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6 (2013, methodology): “(d) HEK293 cells were co-transfected with vectors encoding AMBRA1 together with ULK1–Myc FL (full length) or its deletion mutants encoding the kinase and the proline-rich domains (1829–1,051), and the ULK1 carboxy-terminal domain (11-828).”
Insulin receptor signaling in normal and insulin-resistant states. (2014, background): “mTORC1 also mediates phosphorylation and stabilization of Grb10, leading to feedback inhibition of insulin signaling (Hsu et al. 2011; Yu et al. 2011b).”
TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO (2012, background): “…SKN-1, DAF-16, and other preferentially translated proteins may lead to the transcriptional responses that result from inhibiting either TORC1 or translation, although some of the many phosphorylation targets of TORC1 could also be involved (Hsu et al., 2011; Yu et al., 2011; Zoncu et al., 2011).”
Glc-TOR signalling leads transcriptome reprogramming and meristem activation (2013, neutral): “CHO metabolism (25) Cell wall (25) Redox (19) Protein synthesis (10) Autophagy (7) Biodegradation of xenobiotics (5) Glyoxylate cycle (4) W T G lc 2 h”
A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB (2012, background): “Recent findings suggest that mTORC1 phosphorylates its target proteins at multiple sites (Hsu et al, 2011; Peterson et al, 2011; Yu et al, 2011).”
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer (2023, background): “The first-generation allosteric mTORi includes rapamycin and its analogues, commonly known as rapalogs, which only exert a specifical inhibition towards mTORC1 [291].”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “receptor signaling upstream of Akt and mTORC2, (Hsu et al., 2011; Yu et al., 2011), while S6K1 also suppresses mTORC2 activation through the phosphorylation-dependent degradation of insulin receptor substrate 1 (IRS1) (Harrington et al.”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “…signaling. mTORC1 phosphorylates and activates Grb10, a negative regulator of insulin/IGF-1 receptor signaling upstream of Akt and mTORC2, (Hsu et al., 2011; Yu et al., 2011), while S6K1 also suppresses mTORC2 activation through the phosphorylation-dependent degradation of insulin…”
The PI3K pathway in human disease (2017, positive): “Identiﬁcation of this feedback loop and another involving adaptor protein Grb10 (Hsu et al., 2011; Yu et al., 2011) prompted support for the development of TORKi that target both mTORC1 and mTORC2.”
Rapamycin passes the torch: a new generation of mTOR inhibitors (2011, background): “Several global phospho-proteomic efforts have proposed numerous candidate proteins as direct mTOR substrate”