Kuruvilla, L. | bioRxiv Science

bioRxiv2021

The Lipid Droplet Knowledge Portal: A resource for systematic analyses of lipid droplet biology

Lipid droplets (LDs) are organelles of cellular lipid storage with fundamental roles in energy metabolism and cell membrane homeostasis. There has been an explosion of research into the biology of LDs, in part due to their relevance in diseases of lipid storage, such as atherosclerosis, obesity, type 2 diabetes mellitus, and hepatic steatosis. Consequently, there is an increasing need for a resource that combines large datasets from systematic analyses of LD biology. Here we integrate high-confidence, systematically generated data on studies of LDs in the framework of an online platform named the Lipid Droplet Knowledge Portal. This scalable and interactive portal includes comprehensive datasets, across a variety of cell types, for LD biology, including transcriptional profiles of induced lipid storage, organellar proteomics, genome-wide screen phenotypes, and ties to human genetics. This new resource is a powerful platform that can be utilized to uncover new determinants of lipid storage. HIGHLIGHTS{blacksquare} The LD-Portal is a resource combining datasets from systematic analyses in LD biology {blacksquare}The LD-Portal allows users to query genetic, proteomic, and phenotypic aspects of LD biology {blacksquare}The LD-Portal can be used to discover new facets of lipid storage and LD biology {blacksquare}A crucial function of MSRB3 is uncovered in cholesterol ester storage in LDs

systems biology↗

bioRxiv2020

PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK

Flux through the RAF-MEK-ERK protein kinase cascade is shaped by phosphatases acting on the core components of the pathway. Despite being an established drug target and a hub for crosstalk regulation, little is known about dephosphorylation of MEK, the central kinase within the cascade. Here, we identify PPP6C, a phosphatase frequently mutated or downregulated in melanoma, as a major MEK phosphatase in cells exhibiting oncogenic ERK pathway activation. Recruitment of MEK to PPP6C occurs through an interaction with its associated regulatory subunits. Loss of PPP6C causes hyperphosphorylation of MEK at both activating and crosstalk phosphorylation sites, promoting signaling through the ERK pathway and resistance to the growth inhibitory effects of MEK inhibitors. Recurrent melanoma-associated PPP6C mutations cause MEK hyperphosphorylation, suggesting that they promote disease at least in part by activating the core oncogenic pathway driving melanoma. Collectively, our studies identify a key negative regulator of ERK signaling that may influence susceptibility to targeted cancer therapies.

cancer biology↗