Quantitative Phosphoproteomic Analysis Identifies the Adaptor Protein Grb10 as an mTORC1 Substrate that Negatively Regulates Insulin Signaling

By Yonghao Yu, Sang-Oh Yoon, G. Poulogiannis, Qian Yang, X. Ma, J. Villén, Neil Kubica, G. Hoffman, Lewis C. Cantley, Steven P. Gygi and 1 more. Science, 2011

789 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 evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor–bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal–regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ab63932f66167b1a720fd39193283bace5f82e68

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “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 receptor substrate 1 (IRS1) (”
mTOR signaling in growth control and disease (2012, positive): “Additionally, mTORC1 negatively regulates growth factor signaling by directly phosphorylating IRS1 (Tzatsos and Kandror, 2006) and the RTK inhibitor growth factor receptor-bound protein 10 (Grb10) (Hsu et al., 2011; Yu et al., 2011) as well as by reducing the expression of the platelet-derived growt”
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”
Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1 (2013, background): “This site can be phosphorylated in vitro by PKA (10) and was identified in two recent phospho-proteomic screens for mTORC1-regulated phosphorylation sites (11, 12).”
mTOR: a pharmacologic target for autophagy regulation. (2015, positive): “Furthermore, mTORC1 directly inhibits RTK/PI3K signaling by phosphorylating IRS1 and growth factor–bound protein 10 (GRB10) (54–56).”
TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO (2012, background): “TOR inhibition, rapamycin, and DR seem to promote longevity at least in part by reducingmRNA translation (Bjedov et al., 2010; Kapahi et al., 2010; Kenyon, 2010; Stanfel et al., 2009; Zid et al., 2009).”
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).”
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