mTORC1 controls glycogen synthase kinase 3β nuclear localization and function

Abstract

Glycogen synthase kinase 3β (GSK3β) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3β function by regulation of its nuclear localization. Inhibition of mechanistic target of rapamycin (mTORC1) led to partial redistribution of GSK3β from the cytosol to the nucleus, and GSK3β-dependent reduction of the expression of c-myc and snail. mTORC1 is controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance. Indeed AMPK activation or amino acid deprivation promoted GSK3β nuclear localization in an mTORC1-dependent manner. GSK3β was detected in several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through perturbation of Rab7 resulted in loss of GSK3β from lysosomes, and enhanced GSK3β nuclear localization as well as GSK3β-dependent reduction of c-myc levels. This indicates that GSK3β nuclear localization and function is suppressed by mTORC1, and suggests a new link between metabolic conditions sensed by mTORC1 and GSK3β-dependent regulation of transcriptional networks controlling biomass production.Summary statement (15-30 words)GSK3β nuclear localization and function is negatively regulated by the metabolic and mitogenic sensor mTORC1. mTORC1 control of GSK3β localization requires Rab7 and lysosomal membrane traffic.

Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance

“…Our data indicate that mTOR and nutrient sensing regulate the localization of Pol, and this pathway is more broadly known to affect nuclear-cytoplasmic shuttling of multiple proteins (99-106). For example, PI3K-AKT-mTOR pathway signaling has been shown to prevent nuclear accumulation of glycogen synthase kinase 3 (GSK3) such that inhibition of this pathway leads to a robust increase in nuclear GSK3 (104,105). Furthermore, mTOR complex 1 (mTORC1)-dependent phosphorylation of the transcription factor TFEB (transcription factor EB) promotes its association with members of the 14-3-3 family of proteins, thereby forcing its retention in the cytosol (103).…”

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

“…Our data indicates that mTOR and nutrient sensing regulate the localization of polκ, and this pathway more broadly is known to affect nuclear-cytoplasmic shuttling of multiple proteins (84)(85)(86)(87)(88)(89)(90)(91). For example, PI3K/Akt/mTOR signaling has been shown to prevent nuclear accumulation of glycogen synthase kinase 3β (GSK3β) such that inhibition of this pathway leads to a robust increase in nuclear GSK3β (89,90).…”

The Lysosome Signaling Platform: Adapting With the Times

“…Thus, lysosomes can inform the rest of the cell of its intracellular and extracellular milieu and trigger pathways to help the cell adapt to emerging conditions. This is possible because lysosomes serve as platforms to assemble signaling hubs like mTORC1, AMPK, and GSK3β on their cytosolic surface (Zhang et al, 2013;Carroll and Dunlop, 2017;Bautista et al, 2018;Hesketh et al, 2018;Lamming and Bar-Peled, 2018). We start with a brief illustration of this concept by focusing on the mTORC1 complex and assembly on lysosomes.…”

“…Finally, GSK3β is a kinase with 500 putative substrates and seemingly contradictory functions that may be dictated by GSK3β localization (Beurel et al, 2015); for example, GSK3β localization to lysosomes may promote cell survival and growth, while its localization to the nucleus may promote cell death functions (Bautista et al, 2018). Indeed, its localization to the lysosomes may permit GSK3 to phosphorylate Raptor on Ser859, in response to amino acids, promoting increased Raptor-mTORC1 interactions (Stretton et al, 2015).…”

“…Perhaps central to this evolving picture is the connection between lysosomes and the ever important mTORC1, which uses the lysosome as a signaling platform, integrating nutrient and energy cues to govern the balance between catabolic and anabolic processes within the cell (Lim and Zoncu, 2016). Beyond this, lysosomes serve as a scaffold for AMPK, which counteracts mTORC1, and glycogen synthase kinase-3β (GSK3β), which further integrates growth and apoptotic signals, and even transcription factors such as TFEB that promotes the expression of lysosomal genes in an effort to boost lysosome function in response to stresses like starvation and infection (Sardiello, 2016;Carroll and Dunlop, 2017;Bautista et al, 2018). In this review, we discuss past and recent advancements that place lysosomes as major organizers of cellular signaling, mapping out key pathways that the lysosome integrates to govern diverse cellular functions.…”