Phosphorylated Rho–GDP directly activates mTORC2 kinase towards AKT through dimerization with Ras–GTP to regulate cell migration

Senoo, Hiroshi; Kamimura, Yoichiro; Kimura, Reona; Nakajima, Akihiko; Sawai, Shujiro; Sesaki, Hiromi; Iijima, Miho

doi:10.1038/s41556-019-0348-8

Cited by 68 publications

(72 citation statements)

References 59 publications

(93 reference statements)

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“…This is suggested by observations of intracellular signaling patterns in cells that have been treated with Latrunculin A to disrupt the actin cytoskeleton and exhibited timescales that were of the same order as the cAMP-induced transients observed here [42,43]. Similar timescales also emerged during gradient-induced Ras reorganization or mTORC2 activation [44,45], suggesting that the transition to a lower amplitude state may be related to the organization of the chemotactic machinery. Also, recently proposed models that rely on an oscillatory actin machinery guided by an upstream wavegenerating signaling systems support this view [33,46].…”

Section: Discussionsupporting

confidence: 65%

Receptor-induced transient responses in cells with oscillatory actin dynamics

Negrete

Pumir

Westendorf

et al. 2020

Phys. Rev. Research

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Living cells adjust their sensing and migratory machinery in response to changes in their environment. In this work, we show that cells of the social amoeba Dictyostelium discoideum modulate the dynamical state of their actin cytoskeleton in response to an external pulse of the chemoattractant cyclic adenosine monophosphate (cAMP). In particular, we focus on a population of cells that exhibits noisy oscillatory cycles of actin polymerization and systematically study receptor-induced transitions in their cytoskeletal dynamics. In response to a short external pulse of cAMP, these cells adopt a noisy quiescent state, before returning to their initial, oscillatory dynamics. The response exhibits a biphasic time profile, with a duration that shows strong variability between cells; it can extend as long as approximately twelve oscillation cycles. We propose a model that is based on a generic nonlinear noisy oscillator. Our theoretical analysis suggests that the transient termination of oscillations in response to a receptor stimulus occurs via a Hopf bifurcation.

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Section: Discussionsupporting

confidence: 65%

Receptor-induced transient responses in cells with oscillatory actin dynamics

Negrete

Pumir

Westendorf

et al. 2020

Phys. Rev. Research

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“…However, PDK1 phosphorylation of AKT/PKBR1 requires phosphorylation by mTORC2, so absolute AKT/PKBR1 activity is dependent on mTORC2 (Liao et al, 2010). We also note input of several small GTPases in Dictyostelium (see below) that function downstream of GPCR signaling with direct positive input to mTORC2 (Khanna et al, 2016;Senoo et al, 2019;Rosel, et al, 2012;Charest et al, 2010;Liao et al, 2013).…”

Section: Fig 1 Mtor Complex Regulations In Mammalian and Dictyostelmentioning

confidence: 65%

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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“…Studies have shown that there is functional conservation between mammalian Rac1 and RhoA and Dictyostelium Rac1A/C and RacE, respectively (Filic et al, 2012, Wang et al, 2013a, Wang et al, 2013b. Further evidence for this was put forward in a recent study which shed light on a novel interaction between phosphorylated GDP-bound RacE or RhoA and mTORC2 kinase, resulting in downstream AKT phosphorylation in Dictyostelium and mammalian cells, respectively (Senoo et al, 2019).…”

Section: Spatiotemporal Control Of Signal Transduction Network Regulmentioning

confidence: 96%

The excitable signal transduction networks: movers and shapers of eukaryotic cell migration

Pal¹,

Li²,

Banerjee³

et al. 2019

Int. J. Dev. Biol.

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In response to a variety of external cues, eukaryotic cells display varied migratory modes to perform their physiological functions during development and in the adult. Aberrations in cell migration result in embryonic defects and cancer metastasis. The molecular components involved in cell migration are remarkably conserved between the social amoeba Dictyostelium and mammalian cells. This makes the amoeba an excellent model system for studies of eukaryotic cell migration. These migration-associated components can be grouped into three networks: input, signal transduction and cytoskeletal. In migrating cells, signal transduction events such as Ras or PI3K activity occur at the protrusion tips, referred to as 'front' , whereas events such as dissociation of PTEN from these regions are referred to as 'back' . Asymmetric distribution of such front and back events is crucial for establishing polarity and guiding cell migration. The triggering of these signaling events displays properties of biochemical excitability including all-or-nothing responsiveness to suprathreshold stimuli, refractoriness, and wave propagation. These signal transduction waves originate from a point and propagate towards the edge of the cell, thereby driving cytoskeletal activity and cellular protrusions. Any change in the threshold for network activation alters the range of the propagating waves and the size of cellular protrusions which gives rise to various migratory modes in cells. Thus, this review highlights excitable signal transduction networks as key players for coordinating cytoskeletal activities to drive cell migration in all eukaryotes.

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Phosphorylated Rho–GDP directly activates mTORC2 kinase towards AKT through dimerization with Ras–GTP to regulate cell migration

Cited by 68 publications

References 59 publications

Receptor-induced transient responses in cells with oscillatory actin dynamics

Receptor-induced transient responses in cells with oscillatory actin dynamics

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

The excitable signal transduction networks: movers and shapers of eukaryotic cell migration

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