FIGURE 11.

Proposed model for the role of ESCRTs in regulating GPCR-promoted Akt activation. Binding to agonist (black circle) leads to GPCR-promoted activation of G protein signaling, whereby GDP is exchanged for GTP leading to an active Gα subunit (Gα-GTP) and dissociation of the Gβγ heterodimer. Free Gβγ activates PI3K, which leads to the recruitment of PDK1 and Akt to the plasma membrane where Akt is phosphorylated at Thr-308 by PDK1 and by mTORC2 at Ser-473. Gβγ and PI3K signaling drive DEPTOR degradation likely by promoting DEPTOR targeting into the ILV of the MVBs)via the ESCRT pathway. MVBs eventually fuse with lysosomes where DEPTOR degradation occurs. DEPTOR degradation may facilitate phosphorylation of Akt at Ser-473 by mTORC2. GPCRs can also be targeted into ILVs via ubiquitination and direct interactions with ESCRTs. How DEPTOR is targeted into ILVs of MVBs remains to be determined.