TOR complex 2 (TORC2) in <i>Dictyostelium</i> suppresses phagocytic nutrient capture independently of TORC1-mediated nutrient sensing

Rösel, Daniel; Khurana, Taruna; Majithia, Amit R.; Huang, Xiaolin; Bhandari, Ramanath; Kimmel, Alan R.

doi:10.1242/jcs.077040

Cited by 37 publications

(49 citation statements)

References 55 publications

(115 reference statements)

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“…These mutants have decreased, but not abolished, activation of PkbA and PkbR1 (Lee et al, 2005). In contrast to previously published results, fluid uptake was decreased in TORC2 component mutants (Figure 1E), although not to the same extent as in PkbA-/PkbR1-cells (Rosel et al, 2012).…”

Section: Resultscontrasting

confidence: 99%

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Akt kinases are required for efficient feeding by macropinocytosis inDictyostelium

Williams

Peak‐Chew

Paschke

et al. 2018

Preprint

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Macropinocytosis is an actin-driven process of large-scale, non-specific fluid uptake used for feeding by some cancer cells and the macropinocytosis model organism Dictyostelium discoideum. In Dictyostelium, macropinocytic cups are organised by ‘macropinocytic patches’ in the plasma membrane. These contain activated Ras, Rac and PI(3,4,5)P3 and direct actin polymerisation to their periphery. Here, we show that a classical (PkbA) and a variant (PkbR1) Akt protein kinase acting downstream of PI(3,4,5)P3 are together are near-essential for fluid uptake. This pathway enables the formation of larger macropinocytic patches and macropinosomes, thereby dramatically increasing fluid uptake. Akt targets identified by phosphoproteomics were highly enriched in small G-protein regulators, including the RhoGAP GacG. GacG knockout mutants make few macropinosomes but instead redeploy their cytoskeleton from macropinocytosis to motility, moving rapidly but taking up little fluid. The function of Akt in cell feeding through control of macropinosome size has implications for cancer cell biology.Summary statementDictyostelium amoebae feed by macropinocytosis in a PIP3 dependent manner. In the absence of PI3-kinases or the downstream Akt protein kinases, cells have smaller macropinosomes and nearly abolished fluid uptake.

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Section: Resultscontrasting

confidence: 99%

“…Further experiments using the PI3K1-5- and PkbA-/PkbR1-strains used HL5 medium + 10% FBS, where complications due to starvation are minimised. Further experiments using the TORC2 component and PdkA-mutants are performed in HL5 medium, as this supports their proliferation (Kamimura and Devreotes, 2010; Rosel et al, 2012).…”

Section: Resultsmentioning

confidence: 79%

Akt kinases are required for efficient feeding by macropinocytosis inDictyostelium

Williams

Peak‐Chew

Paschke

et al. 2018

Preprint

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“…However, there is indirect evidence that PA may regulate TOR in Dictyostelium. Both over expression of PLD and exogenously supplied PA suppresses the starvation response in Dyctyostelium (55), and starvation in Dictyostelium inhibits 4E–BP1 phosphorylation (56). Thus, PA suppresses the starvation response that involves inhibition of phosphorylation of an mTORC1 substrate.…”

Section: Conservation Of the Pa Requirement Of Tormentioning

confidence: 99%

Phosphatidic acid and lipid-sensing by mTOR

Foster

2013

Trends in Endocrinology & Metabolism

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Mammalian target of rapamycin (mTOR) has been implicated as a sensor of nutrient sufficiency for dividing cells and is activated by essential amino acids and glucose. However, cells also require lipids for membrane biosynthesis. A central metabolite in the synthesis of membrane phospholipids is phosphatidic acid (PA), which is required for the stability and activity of mTOR complexes. While PA is commonly generated by the phospholipase D-catalyzed hydrolysis of phosphatidylcholine, PA is also generated by diacylglycerol kinases and lysophosphatidic acid acyltransferases, which are at the center of phospholipid biosynthesis. It is proposed that the responsiveness of mTOR/TOR to PA evolved as a means for sensing lipid precursors for membrane biosynthesis prior to doubling the mass of a cell and dividing.

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“…In the presence of rich nutrients, Dictyostelium will rapidly proliferate as individual cells, where mTORC1 remains continuously active (Rosel et al, 2012;Jaiswal and Kimmel, 2019). However, upon nutrient depletion, mTORC1 is inactivated, growth ceases, and Dictyostelium inititiate a developmental program leading to multicellularity (McMains et al, 2008;Devreotes et al, 2013;Loomis, 2015;Rosel et al, 2012;Jaiswal and Kimmel, 2019). Central to development is the elaboration of a complex system for cAMP synthesis, secretion, and relay, mediated by plasma membrane associated G protein-coupled, cAMP receptors (CAR1).…”

Section: Introductionmentioning

confidence: 99%

Integrated actions of mTOR complexes 1 and 2 for growth and development of Dictyostelium

Jaiswal¹,

Majithia²,

Rösel³

et al. 2019

Int. J. Dev. Biol.

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Multi-protein complexes mTORC1 and mTORC2 are required for growth and development of eukaryotes. mTORC1 is a nutrient sensor that integrates metabolic signals and energy state to regulate cell growth/proliferation, whereas, mTORC2 primarily regulates developmental processes. Dictyostelium proliferate in rich growth media, but initiate development upon nutrient depletion. Both mTOR complexes play essential roles in Dictyostelium, where growth and developmental cycles independently require, respectively, mTORC1 or mTORC2. Many protein associations and regulatory pathways for mTORC1 and mTORC2 in Dictyostelium have context similarity to mammalian cells and specificity to inhibition by the immunosuppressive drug rapamycin. In Dictyostelium, mTORC1 function is inactivated upon starvation-induced development, but development is directly induced through rapamycin-mediated inhibition of mTORC1 activity, even in the absence of nutrient withdrawal. Pharmacologic inhibition of mTORC1, in the absence of nutrient loss, has allowed the identification of a class of essential up-regulated, developmentally-associated signaling genes and down-regulated, growth genes. We also review functional pathway regulations that integrate mTORC1/mTORC2 activities and emphasize complexity of small GTPase regulation of mTORC2 activity. Finally, epistases experiments have suggested novel upstream pathway cross-talk in Dictyostelium that requires mTORC1 and mTORC2, but for separate and independent downstream functions.

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TOR complex 2 (TORC2) in Dictyostelium suppresses phagocytic nutrient capture independently of TORC1-mediated nutrient sensing

Cited by 37 publications

References 55 publications

Akt kinases are required for efficient feeding by macropinocytosis inDictyostelium

Akt kinases are required for efficient feeding by macropinocytosis inDictyostelium

Phosphatidic acid and lipid-sensing by mTOR

Integrated actions of mTOR complexes 1 and 2 for growth and development of Dictyostelium

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