Golgi apparatus location and regulation of mTOR is regulated by novel Golgi recruiting protein GRP

Abstract

Mammalian target of rapamycin (mTOR) is a central protein involved in the control of cell growth and metabolism. Dysregulation of mTOR signaling has been closely linked to many human diseases such as cancer, diabetes, obesity cardiovascular diseases, neurological disorders and age related diseases. Although many of the components in the mTOR pathway have been identified, little is known regarding the mechanism of the spatial arrangement of mTOR signaling. Previously, our lab reported that in several common cell lines, a significant amount of mTOR is localized to the membrane of particular sites called the endoplasmic reticulum (ER) and Golgi apparatus. mTOR localization to the ER and Golgi is mediated by novel motifs called the Golgi localization sequence (GLS) and an overlapping endoplasmic reticulum localization sequence (ELS), respectively. Mutation of the GLS or ELS, or over‐expression of these sequences alone, results in inhibition of both mTOR complexes. These results suggest that subcellular localization of mTOR to the Golgi and ER is essential for mTOR signaling. Because GLS lacks apparent membrane association property, we hypothesized that a Golgi membrane protein(s) is responsible for anchoring mTOR to Golgi through the interaction with GLS. We identified a protein that possesses a strong interaction with the GLS. This novel protein carries a Golgi membrane localization domain and directly interacts with and regulates mTOR activity. We therefore named it GLS Receptor Protein (GRP). My data exhibits strong evidence that GRP mediates mTOR localization to the Golgi and is involved in mTOR regulation. Support for this research was provided by the New Jersey Commission on Cancer Research and the National Institute of Health.