Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation

Max L Valenstein^#^{1

2

3

4}, Pranav V Lalgudi^#^{5

6}, Jibril F Kedir^{5

6}, Kendall J Condon^{5

6}, Anna Platzek⁵, Daniel G Freund⁵, Martin S Taylor^{7

8}, Yunhan Xu⁹, Raghu R Chivukula^{10

7

9

11}, David M Sabatini¹²

Affiliations

¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. mlvalenstein@mgb.org.
² Whitehead Institute for Biomedical Research, Cambridge, MA, USA. mlvalenstein@mgb.org.
³ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. mlvalenstein@mgb.org.
⁴ Harvard Medical School, Boston, MA, USA. mlvalenstein@mgb.org.
⁵ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
⁶ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
¹² Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.

^# Contributed equally.

PMID: 39780017
DOI: 10.1038/s41586-024-07974-0

Comment

Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation

Max L Valenstein et al. Nature. 2025 Jan.

. 2025 Jan;637(8045):E11-E14.

doi: 10.1038/s41586-024-07974-0. Epub 2025 Jan 8.

Authors

Affiliations

¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. mlvalenstein@mgb.org.
² Whitehead Institute for Biomedical Research, Cambridge, MA, USA. mlvalenstein@mgb.org.
³ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. mlvalenstein@mgb.org.
⁴ Harvard Medical School, Boston, MA, USA. mlvalenstein@mgb.org.
⁵ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
⁶ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
¹² Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.

^# Contributed equally.

PMID: 39780017
DOI: 10.1038/s41586-024-07974-0

No abstract available

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Conflict of interest statement

Competing interests: D.M.S. is a shareholder of Navitor Pharmaceuticals, which is targeting for therapeutic benefit the amino-acid-sensing pathway upstream of mTORC1.

Comment on

KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing.
Chen J, Ou Y, Yang Y, Li W, Xu Y, Xie Y, Liu Y. Chen J, et al. Nature. 2018 May;557(7706):585-589. doi: 10.1038/s41586-018-0128-9. Epub 2018 May 16. Nature. 2018. PMID: 29769719

References

1. Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020). - DOI - PubMed - PMC
1. Chen, J. et al. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. Nature 557, 585–589 (2018). - DOI - PubMed
1. Wang, D. et al. E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression. Mol. Cell 82, 770–784 (2022). - DOI - PubMed
1. Zhao, T. et al. VWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes. Nat. Commun. 14, 8464 (2023). - DOI - PubMed - PMC
1. Valenstein, M. L. et al. Structure of the nutrient-sensing hub GATOR2. Nature 607, 610–616 (2022). - DOI - PubMed - PMC

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Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation

Affiliations

Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation

Authors

Affiliations

Conflict of interest statement

Comment on

References

Publication types

LinkOut - more resources

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