Phosphorylation of DEPDC5, a component of the GATOR1 complex, releases inhibition of mTORC1 and promotes tumor growth

Padi, Megha; Singh, Neha; Bearss, Jeremiah J.; Olive, Virginie; Song, Jin H.; Cardó-Vila, Marina; Kraft, Andrew S.; Okumura, Kōichi

doi:10.1073/pnas.1904774116

Cited by 17 publications

(16 citation statements)

References 45 publications

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“…The AKT protein kinase is capable of phosphorylating this sequence but prefers R‐X‐R‐X‐X‐(S/T) (Obata et al , 2000). The Pim protein kinases, as well as AKT, play a regulatory role in the control of mRNA translation by modulating the activity of mTORC1 via inducing phosphorylation of proteins regulating this kinase (Zhang et al , 2009; Beharry et al , 2011; Cen et al , 2013; Warfel & Kraft, 2015; Song et al , 2016; Song et al , 2018; Padi et al , 2019) and by phosphorylating directly eIF4B (Cen et al , 2013; Song et al , 2018). A potential alternate mechanism for controlling translation is by phosphorylating EDC3 and regulating mRNA storage and degradation in P‐bodies.…”

Section: Resultsmentioning

confidence: 99%

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

et al. 2021

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Regulation of mRNA stability and translation plays a critical role in determining protein abundance within cells. Processing bodies (P‐bodies) are critical regulators of these processes. Here, we report that the Pim1 and 3 protein kinases bind to the P‐body protein enhancer of mRNA decapping 3 (EDC3) and phosphorylate EDC3 on serine (S)161, thereby modifying P‐body assembly. EDC3 phosphorylation is highly elevated in many tumor types, is reduced upon treatment of cells with kinase inhibitors, and blocks the localization of EDC3 to P‐bodies. Prostate cancer cells harboring an EDC3 S161A mutation show markedly decreased growth, migration, and invasion in tissue culture and in xenograft models. Consistent with these phenotypic changes, the expression of integrin β1 and α6 mRNA and protein is reduced in these mutated cells. These results demonstrate that EDC3 phosphorylation regulates multiple cancer‐relevant functions and suggest that modulation of P‐body activity may represent a new paradigm for cancer treatment.

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Section: Resultsmentioning

confidence: 99%

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

et al. 2021

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“…Furthermore, as discussed above, Akt-mediated phosphorylation of Tsc1 and Tsc2 may have TOR-activation effects in the fly. In other systems, Akt also phosphorylates the endogenous TOR substrate-like inhibitor PRAS40, leading to its dissociation from TOR ( Sancak et al 2007 ; Haar et al 2007 ; Wang et al 2007 , 2008a ; Yang et al 2017 ), although in flies this appears to be relevant only in the ovary ( Pallares-Cartes et al 2012 ); Akt also inhibits GATOR1 in mammalian cell culture ( Padi et al 2019 ), promoting TOR recruitment to the lysosome. Thus, insulin signaling promotes cell growth and proliferation via control of gene expression and protein synthesis, in large part via Akt, which regulates FOXO, Myc, and the TOR pathway.…”

Section: Regulation Of Cell Size and Numbermentioning

confidence: 99%

Regulation of Body Size and Growth Control

Texada¹,

Kaburagi²,

Rewitz³

2020

Genetics

118

146

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The control of body and organ growth is essential for the development of adults with proper size and proportions, which is important for survival and reproduction. In animals, adult body size is determined by the rate and duration of juvenile growth, which are influenced by the environment. In nutrient-scarce environments in which more time is needed for growth, the juvenile growth period can be extended by delaying maturation, whereas juvenile development is rapidly completed in nutrient-rich conditions. This flexibility requires the integration of environmental cues with developmental signals that govern internal checkpoints to ensure that maturation does not begin until sufficient tissue growth has occurred to reach a proper adult size. The Target of Rapamycin (TOR) pathway is the primary cell-autonomous nutrient sensor, while circulating hormones such as steroids and insulin-like growth factors are the main systemic regulators of growth and maturation in animals. We discuss recent findings in Drosophila melanogaster showing that cell-autonomous environment and growth-sensing mechanisms, involving TOR and other growth-regulatory pathways, that converge on insulin and steroid relay centers are responsible for adjusting systemic growth, and development, in response to external and internal conditions. In addition to this, proper organ growth is also monitored and coordinated with whole-body growth and the timing of maturation through modulation of steroid signaling. This coordination involves interorgan communication mediated by Drosophila insulin-like peptide 8 in response to tissue growth status. Together, these multiple nutritional and developmental cues feed into neuroendocrine hubs controlling insulin and steroid signaling, serving as checkpoints at which developmental progression toward maturation can be delayed. This review focuses on these mechanisms by which external and internal conditions can modulate developmental growth and ensure proper adult body size, and highlights the conserved architecture of this system, which has made Drosophila a prime model for understanding the coordination of growth and maturation in animals.

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“…Both GATOR1 [61] and FLCN-FNIP2 [62] appear to be regulated by phosphorylation by other Ser/Thr kinases, although the structural effects of phosphorylation on either of these complexes are not yet clear. GATOR1 is additionally regulated through interactions with two other protein complexes, KICSTOR and GATOR2.…”

Section: Regulating the Regulatorsmentioning

confidence: 99%

Structural Insights into TOR Signaling

Tafur

Kefauver

Loewith

2020

Genes

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The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects of cellular homeostasis and orchestrate the cellular responses to diverse environmental challenges. Interest in understanding TOR signaling is further motivated by observations that link aberrant TOR signaling to a variety of diseases, ranging from epilepsy to cancer. In the last few years, driven in large part by recent advances in cryo-electron microscopy, there has been an explosion of available structures of (m)TORC1 and its regulators, as well as several (m)TORC2 structures, derived from both yeast and mammals. In this review, we highlight and summarize the main findings from these reports and discuss both the fascinating and unexpected molecular biology revealed and how this knowledge will potentially contribute to new therapeutic strategies to manipulate signaling through these clinically relevant pathways.

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Phosphorylation of DEPDC5, a component of the GATOR1 complex, releases inhibition of mTORC1 and promotes tumor growth

Cited by 17 publications

References 45 publications

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

Regulation of Body Size and Growth Control

Structural Insights into TOR Signaling

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