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

Abstract

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.

Ras, PI3K and mTORC2 – three's a crowd?

“…In mammalian cells, mTORC2 controls the actin cytoskeleton and cell migration in addition to several other cellular functions, such as ion transport, cell-substrate adhesion, cellular survival, proliferation and growth, as well as metabolism (Fig. 3) (Jacinto et al, 2004;Zhou and Huang, 2010;Liu et al, 2010;Gulhati et al, 2011;Farhan et al, 2015;Chen et al, 2015a,b;Yin et al, 2016;Sato et al, 2016;Roelants et al, 2017;Xie et al, 2018;Jaiswal et al, 2019;Liu and Sabatini, 2020). Similar to that in Dictyostelium, mTORC2-mediated regulation of the actin cytoskeleton in mammalian cells is involved in controlling the motility, migration and chemotaxis of many types of cell, including neutrophils and human cancer cells (Zhou and Huang, 2010;Gulhati et al, 2011;Liu and Parent, 2011;Kim et al, 2017;Holroyd and Michie, 2018;Liu and Sabatini, 2020).…”

Possible Involvement of the Nutrient and Energy Sensors mTORC1 and AMPK in Cell Fate Diversification in a Non-Metazoan Organism

“…This response is conserved when amoebae of D. discoideum are starved: mTORC1 activity is rapidly down-regulated and AMPK activity increases ( Rosel et al, 2012 ; Jaiswal and Kimmel, 2019 ); cell division and DNA replication soon cease, autophagosomes appear in increased numbers ( Zimmerman and Weijer, 1993 ; King et al, 2011 ) and autophagy genes are upregulated ( Jaiswal et al, 2019 ). At the same time, development is initiated and transcription switches from the growth transcriptome to the early aggregative transcriptome ( Jaiswal and Kimmel, 2019 ).…”

The WIPI Gene Family and Neurodegenerative Diseases: Insights From Yeast and Dictyostelium Models

“…Dictyostelium belongs to the amoebozoa group, and although this group of organisms diverged before the opistokonta (fungi and animals), it retains many features of animal cells that have been lost during the evolution of fungi. Cell motility and chemotaxis, phagocytosis and macropynocytosis are very similar to those observed in animal cells and Dictyostelium presents a multicellular stage that allows the study of cell differentiation and morphogenesis (see this series of reviews collected in a special issue dedicated to Dictyostelium in IJDB ( Araki and Saito, 2019 ; Batsios et al, 2019 ; Bloomfield, 2019 ; Bozzaro, 2019 ; Consalvo et al, 2019 ; Escalante and Cardenal-Muñoz, 2019 ; Farinholt et al, 2019 ; Fey et al, 2019 ; Fischer and Eichinger, 2019 ; Ishikawa-Ankerhold and Müller-Taubenberger, 2019 ; Jaiswal et al, 2019 ; Kawabe et al, 2019 ; Kay et al, 2019 ; Knecht et al, 2019 ; Kundert and Shaulsky, 2019 ; Kuspa and Shaulsky, 2019 ; Medina et al, 2019 ; Nanjundiah, 2019 ; Pal et al, 2019 ; Pearce et al, 2019 ; Pergolizzi et al, 2019 ; Schaf et al, 2019 ; Vines and King, 2019 ). Individual Dictyostelium cells ingest bacteria and yeasts in soil and the transition to a multicellular state, triggered when the food source is depleted, is accomplished by aggregation of preexisting cells.…”