dictyNews
Electronic Edition
Volume 46, number 31
November 06, 2020

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Abstracts
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Hetero-oligomerization of Rho and Ras GTPases Connects GPCR 
Activation to mTORC2-AKT Signaling

Hiroshi Senoo, May Wai, Hideaki T. Matsubayashi, Hiromi Sesaki 
and Miho Iijima

Department of Cell Biology, Johns Hopkins University School of 
Medicine, Baltimore, Maryland, USA, 21205


Cell reports, accepted

The activation of G protein-coupled receptors (GPCR) leads to 
the activation of mTORC2 in cell migration and metabolism. 
However, the mechanism that links GPCRs to mTORC2 remains 
unknown. Here, using Dictyostelium cells, we show that GPCR-
mediated chemotactic stimulation induces hetero-oligomerization 
of phosphorylated GDP-bound Rho GTPase and GTP-bound Ras 
GTPase in directed cell migration. The Rho-Ras hetero-oligomers 
directly and specifically activate mTORC2 toward AKT in cells 
and biochemical reconstitution using purified proteins in vitro. The 
Rho-Ras hetero-oligomers do not activate ERK/MAPK, another 
kinase that functions downstream of GPCRs and Ras. Human 
KRas4B functionally replace Dictyostelium Ras in mTORC2 
activation. In contrast to GDP-Rho, GTP-Rho antagonizes 
mTORC2-AKT signaling by inhibiting the oligomerization of 
GDP-Rho with GTP-Ras. These data reveal that GPCR- 
stimulated hetero-oligomerization of Rho and Ras provides a 
critical regulatory step that controls mTORC2-AKT signaling.


submitted by: Hiroshi Senoo [[log in to unmask]]
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[End dictyNews, volume 46, number 31]