Phosphoproteomic Analysis Identifies Grb10 as an mTORC1 Substrate That Negatively Regulates Insulin Signaling
Yonghao Yu,Sang-Oh Yoon,George Poulogiannis,Qian Yang,Xiaoju Max Ma,Judit Villén,Neil Kubica,Gregory R. Hoffman,Lewis C. Cantley,Steven P. Gygi,John Blenis +10 more
TL;DR: A search for substrates of a growth-promoting kinase revealed a regulatory feedback loop involved in tumor suppression, and large-scale quantitative phosphoproteomics experiments were used to define the signaling networks downstream of mTORC1 and m TORC2.
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Abstract: 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.
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mTOR: A pathogenic signaling pathway in developmental brain malformations
TL;DR: Investigation of mTOR signaling in these disorders provides for the first time exciting future avenues for assessment of biomarkers, patient stratification and prognostic measures as well as the opportunity for targeted therapy to regulate mTOR activity across all age groups.
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Connecting mTORC1 signaling to SREBP-1 activation.
Inan Bakan,Mathieu Laplante +1 more
TL;DR: The discovery of a connection between mTORC1 and SREBP-1 opens a new chapter in the understanding of the molecular mechanisms regulating de-novo lipogenesis, which is key for the development of new tools to treat NAFLD and its complications.
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Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ.
Sarit Schwartz,John Wongvipat,Cath Trigwell,Urs Hancox,Brett S. Carver,Vanessa Rodrik-Outmezguine,Marie Will,Paige Yellen,Elisa de Stanchina,José Baselga,Howard I. Scher,Simon T. Barry,Charles L. Sawyers,Sarat Chandarlapaty,Sarat Chandarlapaty,Neal Rosen,Neal Rosen +16 more
TL;DR: In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity, and combined inhibition of both PI2K isoforms and androgen receptors results in major tumor regressions.
264
Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis
Pengda Liu,Wenjian Gan,Hiroyuki Inuzuka,Adam S. Lazorchak,Daming Gao,Omotooke Arojo,Dou Liu,Lixin Wan,Bo Zhai,Yonghao Yu,Yonghao Yu,Min Yuan,Byeong Mo Kim,Shavali Shaik,Suchithra Menon,Steven P. Gygi,Tae Ho Lee,John M. Asara,Brendan D. Manning,John Blenis,Bing Su,Wenyi Wei +21 more
TL;DR: Results reveal a Sin1-phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the m TORC1–S6K–Sin1 signalling axis might cause aberrant hyper-activation of the mtorC2–Akt pathway, which facilitates tumorigenesis.
Emerging role of autophagy in kidney function, diseases and aging
Tobias B. Huber,Charles L. Edelstein,Björn Hartleben,Ken Inoki,Man Jiang,Daisuke Koya,Shinji Kume,Wilfred Lieberthal,Nicolas Pallet,Alejandro Quiroga,Kameswaran Ravichandran,Katalin Susztak,Sei Yoshida,Zheng Dong +13 more
TL;DR: Recent insights on the role of autophagy in kidney physiology and diseases are summarized alluding to possible novel intervention strategies for treating specific kidney disorders by modifying Autophagy.
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