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The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways
Andrea Gubas1, Christina Karantanou2,3, Doris Popovic1
1Faculty of Medicine, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt am Main, Germany.
FEBS Letters
|January 16, 2021
Summary
Pleckstrin homology domain-containing family member 1 (PLEKHM1) is regulated by both mTOR and ERK2 phosphorylation. This dual control integrates growth factor and amino acid signaling pathways at the lysosome.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Lysosomes are central signaling hubs integrating endocytic and autophagic pathways.
- Pleckstrin homology domain-containing family member 1 (PLEKHM1) is an adaptor protein crucial for lysosome fusion.
- The regulatory mechanisms controlling PLEKHM1 function at the lysosome remain largely unknown.
Purpose of the Study:
- To investigate the regulation of PLEKHM1 function at the lysosome.
- To identify the signaling pathways that control PLEKHM1 activity.
- To understand how PLEKHM1 integrates cellular metabolic cues.
Main Methods:
- Co-immunoprecipitation assays to detect protein interactions.
- In vitro kinase assays to confirm direct phosphorylation.
- Development and use of phosphospecific antibodies for analyzing phosphorylation sites.
Main Results:
- PLEKHM1 directly interacts with and is phosphorylated by mTOR.
- The Ser432/S435 motif on PLEKHM1 is a direct phosphorylation target of ERK2.
- ERK2-mediated phosphorylation of PLEKHM1 is dependent on growth factor signaling.
- This dual phosphorylation occurs in a conserved region of PLEKHM1.
Conclusions:
- PLEKHM1 is dually regulated by mTOR and ERK2 at a conserved phosphorylation site.
- This dual regulation integrates amino acid-sensing (mTOR) and growth factor-sensing (ERK2) pathways.
- PLEKHM1 acts as a critical molecular node connecting cellular metabolism and lysosomal function.
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