BMB Reports : eISSN 1976-670X

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Fig. 2. (A) Signaling network that regulate TorC2. TorC2 activity is regulated either at the level of the subunit assembly or the TorC kinase activity. The kinase IKK activates TorC2 (i) but several other kinases such as GSK3 and S6K1 inhibit TorC2 (ii and iii). In Dictyostelium, Ras and Rap proteins function positively at the upstream of TorC2 (iv) and PP2A/B56 seems necessary for Ras activation (viii). Interestingly, TorC2 may activate PP2A/B56 through PKA and thus potentially form positive feedback loop (iv, vi, and viii). In addition to PKA, TorC2 activates Akt (v). Akt, unlike PKA, is a target of PP2A/B56 mediated inhibition (vii). (B) Regulatory network that orchestrate TorC2 mediated Cytoskeletal remodeling. In Dictyostelium, TorC2 activates Akt kinases, which in turn phosphorylate multiple proteins that mediate F-Actin remodeling at the leading edge of a migrating cell (i). In addition, Akt may also modulate Talin/Vinculin containing adhesion complexes (ii). The Talin/Vinculin complex may activate TorC2 and thus may form a positive feedback loop (iii). TorC2 may affect rear end retraction through either activating PKA (iv) or modulating Paxillin/FAK adhesion complex (v). Considering that these two singling axes are antagonistic, the signaling output from TorC2 to the Rho mediated rear end retraction is likely dependent on the strength of each signaling in a cell type specific manner. (C) PP2A/B56 mediated regulation of TorC1 signaling network. A number of kinases that are known to modulate the TorC1 activity are also known to be targets of PP2A/B56. Kinases that regulate the Rheb GAP protein TSC1/2, the critical upstream regulator of TorC1 activity (i), include Akt, ERK1/2, and AMPK. These kinases are the known targets of PP2A (ii and iii). Another kinase MAP4K3 is known to regulate the small GTPase Rag and thus regulate TorC1 and is the target of PP2A/B56 (iv). Lastly, PP2A/B56 inhibits TorC1 target S6K1 (v). The types of B56 isoforms and their targets are denoted in the diagram. (D) TorC1 signaling network and the cytoskeletal remodeling in the context of cell migration. In addition to the previously described role of TorC2 in the cytoskeletal remodeling (Fig. 2B), TorC2 may also affect the process by activating TorC1 through Akt (i), which will eventually inhibit TorC2 through S6K1 as a negative feedback loop. S6K1, a TorC1 downstream signaling components, may activate Paxillin/FAK including adhesion complex (ii) and thus activate Rho small GTPase (iii). Another well-characterized target of TorC1 is TAP42, through which TorC1 may inhibit PP2A/B56 (iv). Inhibition of PP2A/B56 would derepress Rho activity at the rear cell end. In addition, S6K1 was shown to affect lamellipodia formation through affecting expression of small GTPases RhoA, Rac, and Cdc42 (v). Finally, TorC1/S6K1 signaling axis was shown to affect caveolin-enriched F-Actin structure at the leading edge (vi).
BMB Reports 2017;50:437~444
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