Faculty of Medicine, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt am Main, Germany.
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Medicine, Frankfurt, Germany.
FEBS Lett. 2021 Apr;595(7):864-880. doi: 10.1002/1873-3468.14041. Epub 2021 Feb 28.
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 coprecipitates with, and is directly phosphorylated by, mTOR. Using a phosphospecific 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.
溶酶体是细胞信号枢纽，位于内吞和自噬途径的交汇点，在这里内容物被降解和回收。具有 PH 结构域的家族成员 1（PLEKHM1）作为衔接蛋白促进内吞体和自噬体与溶酶体融合。然而，PLEKHM1 在溶酶体中的功能如何被控制尚不清楚。在此，我们发现 PLEKHM1 与 mTOR 共沉淀，并直接被其磷酸化。使用针对 PLEKHM1 的 Ser432/S435 磷酸化的特异性抗体，我们发现同样的模体是 ERK2 介导的、生长因子依赖性磷酸化的直接靶点。PLEKHM1 在高度保守区域的这种双重调节表明，生长因子和氨基酸感应途径的汇聚，将 PLEKHM1 置于细胞代谢的关键节点。
