PLEKHM1 is a direct target for both mTOR and MAPK pathways

The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Previously, we identified the adaptor protein PLEKHM1, which facilitates the fusion of endocytic and autophagic vesicles with the lysosome. It is unclear how the function of PLEKHM1 at the lysosome is controlled. Herein, we show that PLEKHM1 co-precipitates with mTOR and its regulatory partners. PLEKHM1 is directly phosphorylated by mTOR at a proline-directed dual serine motif. Using a phospho-specific antibody that recognizes PLEKHM1 when phosphorylated at Serine432/Ser435, 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 two major cellular metabolic pathways.