MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation

Mohamad-Ali Fawal; Marta Brandt; Nabil Djouder

doi:10.1016/j.devcel.2015.02.010

MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation

Dev Cell. 2015 Apr 6;33(1):67-81. doi: 10.1016/j.devcel.2015.02.010. Epub 2015 Mar 26.

Authors

Mohamad-Ali Fawal¹, Marta Brandt¹, Nabil Djouder²

Affiliations

¹ Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain.
² Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain. Electronic address: ndjouder@cnio.es.

PMID: 25816988
DOI: 10.1016/j.devcel.2015.02.010

Abstract

Ras homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Amino Acids / pharmacology*
Animals
Blotting, Western
Cells, Cultured
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
Endocytosis / drug effects
Fibroblasts / cytology
Fibroblasts / drug effects
Fibroblasts / metabolism
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Immunoprecipitation
Integrases / metabolism
Intercellular Signaling Peptides and Proteins / pharmacology
Lysosomes / metabolism
Mass Spectrometry
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Knockout
Monomeric GTP-Binding Proteins / antagonists & inhibitors
Monomeric GTP-Binding Proteins / genetics
Monomeric GTP-Binding Proteins / metabolism*
Multiprotein Complexes / antagonists & inhibitors
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism*
Neuropeptides / antagonists & inhibitors
Neuropeptides / genetics
Neuropeptides / metabolism*
Nuclear Proteins / physiology*
RNA, Small Interfering / genetics
RNA-Binding Proteins
Ras Homolog Enriched in Brain Protein
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins / metabolism

Substances

Amino Acids
Intercellular Signaling Peptides and Proteins
Mcrs1 protein, mouse
Multiprotein Complexes
Neuropeptides
Nuclear Proteins
RNA, Small Interfering
RNA-Binding Proteins
Ras Homolog Enriched in Brain Protein
Rheb protein, mouse
TSC2 protein, human
Tsc2 protein, mouse
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins
Adenosine Triphosphate
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Cre recombinase
Integrases
Monomeric GTP-Binding Proteins