KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1

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KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1

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Title: KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1
Author: Wolfson, Rachel L.; Chantranupong, Lynne; Wyant, Gregory A.; Gu, Xin; Orozco, Jose M.; Shen, Kuang; Condon, Kendall J.; Petri, Sabrina; Kedir, Jibril; Scaria, Sonia M.; Abu-Remaileh, Monther; Frankel, Wayne N.; Sabatini, David M.

Note: Order does not necessarily reflect citation order of authors.

Citation: Wolfson, R. L., L. Chantranupong, G. A. Wyant, X. Gu, J. M. Orozco, K. Shen, K. J. Condon, et al. 2017. “KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1.” Nature 543 (7645): 438-442. doi:10.1038/nature21423. http://dx.doi.org/10.1038/nature21423.
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Abstract: The mechanistic target of rapamycin complex 1 kinase (mTORC1) is a central regulator of cell growth that responds to diverse environmental signals and is deregulated in many human diseases, including cancer and epilepsy1–3. Amino acids are a key input, and act through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation4. Multiple protein complexes regulate the Rag GTPases in response to amino acids, including GATOR1, a GTPase activating protein for RagA, and GATOR2, a positive regulator of unknown molecular function. Here, we identify a four-membered protein complex (KICSTOR) composed of the KPTN, ITFG2, C12orf66, and SZT2 gene products as required for amino acid or glucose deprivation to inhibit mTORC1 in cultured cells. In mice lacking SZT2, mTORC1 signaling is increased in several tissues, including in neurons in the brain. KICSTOR localizes to lysosomes; binds to GATOR1 and recruits it, but not GATOR2, to the lysosomal surface; and is necessary for the interaction of GATOR1 with its substrates, the Rag GTPases, and with GATOR2. Interestingly, several KICSTOR components are mutated in neurological diseases associated with mutations that lead to hyperactive mTORC1 signaling5–10. Thus, KICSTOR is a lysosome-associated negative regulator of mTORC1 signaling that, like GATOR1, is mutated in human disease11,12.
Published Version: doi:10.1038/nature21423
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360989/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375206
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