The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways

Andrea Gubas; Christina Karantanou; Doris Popovic; Georg Tascher; Marina E. Hoffmann; Anna Platzek; Nina Dawe; Ivan Dikic; Daniela S. Krause; David G. McEwan

doi:10.1002/1873-3468.14041

The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways

Andrea Gubas, Christina Karantanou, Doris Popovic, Georg Tascher, Marina E. Hoffmann, Anna Platzek, Nina Dawe, Ivan Dikic (Lead / Corresponding author), Daniela S. Krause (Lead / Corresponding author), David G. McEwan (Lead / Corresponding author)

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

139 Downloads (Pure)

Abstract

The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain-containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 co-precipitates with, and is directly phosphorylated by, mTOR. Using a phospho-specific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2-mediated phosphorylation in a growth factor-dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor- and amino acid-sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

Original language	English
Pages (from-to)	864-880
Number of pages	17
Journal	FEBS Letters
Volume	595
Issue number	7
Early online date	16 Jan 2021
DOIs	https://doi.org/10.1002/1873-3468.14041
Publication status	Published - Apr 2021

ASJC Scopus subject areas

Biophysics
Structural Biology
Biochemistry
Molecular Biology
Genetics
Cell Biology

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10.1002/1873-3468.14041Licence: CC BY

Final Published VersionFinal published version, 5.08 MBLicence: CC BY

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title = "The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways",

abstract = "The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain-containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 co-precipitates with, and is directly phosphorylated by, mTOR. Using a phospho-specific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2-mediated phosphorylation in a growth factor-dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor- and amino acid-sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.",

author = "Andrea Gubas and Christina Karantanou and Doris Popovic and Georg Tascher and Hoffmann, {Marina E.} and Anna Platzek and Nina Dawe and Ivan Dikic and Krause, {Daniela S.} and McEwan, {David G.}",

note = "Funding Information: The anti‐LAMP‐2 (H4B4) antibody was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa. This work was supported by grants from Tenovus Scotland (T16/44) and a Wellcome Trust Seed Award (202061/Z/16/Z) to DGM and institutional funds of the Georg‐Speyer‐Haus to D.S.K. The Georg‐Speyer‐Haus is funded jointly by the German Federal Ministry of Health (BMG) and the Ministry of Higher Education, Research and the Arts of the State of Hessen (HMWK). Publisher Copyright: {\textcopyright} 2021 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",

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doi = "10.1002/1873-3468.14041",

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AU - Gubas, Andrea

AU - Karantanou, Christina

AU - Popovic, Doris

AU - Tascher, Georg

AU - Hoffmann, Marina E.

AU - Platzek, Anna

AU - Dawe, Nina

AU - Dikic, Ivan

AU - Krause, Daniela S.

AU - McEwan, David G.

N1 - Funding Information: The anti‐LAMP‐2 (H4B4) antibody was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa. This work was supported by grants from Tenovus Scotland (T16/44) and a Wellcome Trust Seed Award (202061/Z/16/Z) to DGM and institutional funds of the Georg‐Speyer‐Haus to D.S.K. The Georg‐Speyer‐Haus is funded jointly by the German Federal Ministry of Health (BMG) and the Ministry of Higher Education, Research and the Arts of the State of Hessen (HMWK). Publisher Copyright: © 2021 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

PY - 2021/4

Y1 - 2021/4

N2 - The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain-containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 co-precipitates with, and is directly phosphorylated by, mTOR. Using a phospho-specific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2-mediated phosphorylation in a growth factor-dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor- and amino acid-sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

AB - The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain-containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 co-precipitates with, and is directly phosphorylated by, mTOR. Using a phospho-specific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2-mediated phosphorylation in a growth factor-dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor- and amino acid-sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

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The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways

Abstract

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Understanding the Role and Regulation of Lysosomal Adaptor Proteins During Infection

Determining the Molecular Mechanisms Regulating Lysosome Damage and Repair Pathways (Seed Award)

Cite this

The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways

Abstract

ASJC Scopus subject areas

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Other files and links

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Projects

Understanding the Role and Regulation of Lysosomal Adaptor Proteins During Infection

Determining the Molecular Mechanisms Regulating Lysosome Damage and Repair Pathways (Seed Award)

Cite this