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In vivo evidence for mTORC2-mediated actin cytoskeleton rearrangement in neurons.

Angliker N, Rüegg MA - Bioarchitecture (2013 Jul-Aug)

Bottom Line: The mammalian target of rapamycin (mTOR) assembles into two distinct multi-protein complexes called mTORC1 and mTORC2.While mTORC1 controls the signaling pathways important for cell growth, the physiological function of mTORC2 is only partially known.We discuss that this phenotype might be based on the perturbed regulation of the actin cytoskeleton and the lack of activation of several PKC isoforms.

View Article: PubMed Central - PubMed

Affiliation: Biozentrum; University of Basel; Basel, Switzerland.

ABSTRACT
The mammalian target of rapamycin (mTOR) assembles into two distinct multi-protein complexes called mTORC1 and mTORC2. While mTORC1 controls the signaling pathways important for cell growth, the physiological function of mTORC2 is only partially known. Here we comment on recent work on gene-targeted mice lacking mTORC2 in the cerebellum or the hippocampus that provided strong evidence that mTORC2 plays an important role in neuron morphology and synapse function. We discuss that this phenotype might be based on the perturbed regulation of the actin cytoskeleton and the lack of activation of several PKC isoforms. The fact that PKC isoforms and their targets have been implicated in neurological disease including spinocerebellar ataxia and that they have been shown to affect learning and memory, suggests that aberration of mTORC2 signaling might be involved in diseases of the brain.

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Related in: MedlinePlus

Figure 1. Model for the regulation of actin cytoskeletal dynamics by mTORC2. Activation of PKC by mTORC2 results in a phosphorylation of GAP-43-like proteins, MARCKS and GAP-43, which dissociate form PI(4,5)P2 rafts and make PI(4,5)P2 accessible for other actin cytoskeletal regulating proteins or hydrolysis. In parallel, PKC causes free-barbed actin filament ends by phosphorylating adducin which promotes actin dynamics. Association of mTORC2 with Tiam1 and the regulation of its downstream targets may also contribute to actin filament stabilization. In this model, mTORC2 affects depolymerization and polymerization of actin at different sites by controlling PKC- and Tiam1-signaling.
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Figure 1: Figure 1. Model for the regulation of actin cytoskeletal dynamics by mTORC2. Activation of PKC by mTORC2 results in a phosphorylation of GAP-43-like proteins, MARCKS and GAP-43, which dissociate form PI(4,5)P2 rafts and make PI(4,5)P2 accessible for other actin cytoskeletal regulating proteins or hydrolysis. In parallel, PKC causes free-barbed actin filament ends by phosphorylating adducin which promotes actin dynamics. Association of mTORC2 with Tiam1 and the regulation of its downstream targets may also contribute to actin filament stabilization. In this model, mTORC2 affects depolymerization and polymerization of actin at different sites by controlling PKC- and Tiam1-signaling.

Mentions: The change in the phosphorylation state of MARCKS and adducin in rictor knockout mice will shift the equilibrium between membrane/actin-bound and the cytosolic form of MARCKS and adducin toward membrane and the actin-bound form, respectively (Fig. 1). A shift in the relative amount of phosphorylated MARCKS has been implicated in dendrite morphology. For example, hyperactivity of PKC and thus hyperphosphorylation of MARCKS has been shown to contribute to the strongly reduced dendritic arborization observed upon forebrain-specific deletion of the gene cluster encoding the γ-protocadherins.37 Reduction of dendritic arborization by knockdown of MARCKS or overexpression of a “dominant-negative” (e.g., phosphomimetic) form of MARCKS was also reported in cultured hippocampal neurons.38 These results argue that the loss of phosphorylation of MARCKS in rictor-depleted neurons would result in exuberant dendritic branching. Indeed, rictor-knockout Purkinje cells show an increased number of primary dendrites.18


In vivo evidence for mTORC2-mediated actin cytoskeleton rearrangement in neurons.

Angliker N, Rüegg MA - Bioarchitecture (2013 Jul-Aug)

Figure 1. Model for the regulation of actin cytoskeletal dynamics by mTORC2. Activation of PKC by mTORC2 results in a phosphorylation of GAP-43-like proteins, MARCKS and GAP-43, which dissociate form PI(4,5)P2 rafts and make PI(4,5)P2 accessible for other actin cytoskeletal regulating proteins or hydrolysis. In parallel, PKC causes free-barbed actin filament ends by phosphorylating adducin which promotes actin dynamics. Association of mTORC2 with Tiam1 and the regulation of its downstream targets may also contribute to actin filament stabilization. In this model, mTORC2 affects depolymerization and polymerization of actin at different sites by controlling PKC- and Tiam1-signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4201605&req=5

Figure 1: Figure 1. Model for the regulation of actin cytoskeletal dynamics by mTORC2. Activation of PKC by mTORC2 results in a phosphorylation of GAP-43-like proteins, MARCKS and GAP-43, which dissociate form PI(4,5)P2 rafts and make PI(4,5)P2 accessible for other actin cytoskeletal regulating proteins or hydrolysis. In parallel, PKC causes free-barbed actin filament ends by phosphorylating adducin which promotes actin dynamics. Association of mTORC2 with Tiam1 and the regulation of its downstream targets may also contribute to actin filament stabilization. In this model, mTORC2 affects depolymerization and polymerization of actin at different sites by controlling PKC- and Tiam1-signaling.
Mentions: The change in the phosphorylation state of MARCKS and adducin in rictor knockout mice will shift the equilibrium between membrane/actin-bound and the cytosolic form of MARCKS and adducin toward membrane and the actin-bound form, respectively (Fig. 1). A shift in the relative amount of phosphorylated MARCKS has been implicated in dendrite morphology. For example, hyperactivity of PKC and thus hyperphosphorylation of MARCKS has been shown to contribute to the strongly reduced dendritic arborization observed upon forebrain-specific deletion of the gene cluster encoding the γ-protocadherins.37 Reduction of dendritic arborization by knockdown of MARCKS or overexpression of a “dominant-negative” (e.g., phosphomimetic) form of MARCKS was also reported in cultured hippocampal neurons.38 These results argue that the loss of phosphorylation of MARCKS in rictor-depleted neurons would result in exuberant dendritic branching. Indeed, rictor-knockout Purkinje cells show an increased number of primary dendrites.18

Bottom Line: The mammalian target of rapamycin (mTOR) assembles into two distinct multi-protein complexes called mTORC1 and mTORC2.While mTORC1 controls the signaling pathways important for cell growth, the physiological function of mTORC2 is only partially known.We discuss that this phenotype might be based on the perturbed regulation of the actin cytoskeleton and the lack of activation of several PKC isoforms.

View Article: PubMed Central - PubMed

Affiliation: Biozentrum; University of Basel; Basel, Switzerland.

ABSTRACT
The mammalian target of rapamycin (mTOR) assembles into two distinct multi-protein complexes called mTORC1 and mTORC2. While mTORC1 controls the signaling pathways important for cell growth, the physiological function of mTORC2 is only partially known. Here we comment on recent work on gene-targeted mice lacking mTORC2 in the cerebellum or the hippocampus that provided strong evidence that mTORC2 plays an important role in neuron morphology and synapse function. We discuss that this phenotype might be based on the perturbed regulation of the actin cytoskeleton and the lack of activation of several PKC isoforms. The fact that PKC isoforms and their targets have been implicated in neurological disease including spinocerebellar ataxia and that they have been shown to affect learning and memory, suggests that aberration of mTORC2 signaling might be involved in diseases of the brain.

Show MeSH
Related in: MedlinePlus