Regulation of Blood–Testis Barrier (BTB) Dynamics during Spermatogenesis via the “Yin” and “Yang” Effects of Mammalian Target of Rapamycin Complex 1 (mTORC1) and mTORC2 - International Review of Cell and Molecular Biology - page 329

reduced mTORC2, this thus suggests that small GTPase Rac1 and Rho are
possible mediators of mTORC2 in controlling actin organization ( Jacinto
et al., 2004 ). In fact, these small GTPases are likely downstream molecules
of PKC-α ( Fig. 6.3 ). This notion was supported by studies revealing that the
Rho-induced actin rearrangement, such as stress-fibers formation, in endo-
thelial cells was PKC-α-dependent. It was shown that upon treatment of
TNF-α or thrombin, actin reorganization was induced and such actin reor-
ganization was found to be mediated by activation of Rho GTPase activator
p115RhoGEF (a guanine nucleotide exchange factor for Rho GTPase) by
PKC-α ( Holinstat et al., 2003 ; Peng et al., 2011 ). Moreover, it is known
that PKC-α is also able to activate Rho by negatively regulating the Rho
inhibitor, Rho-GDP guanine nucleotide dissociation inhibitor (GDI), via
phosphorylation ( Mehta et al., 2001 ). In short, the above studies suggest that
small GTPases, such as Rho and Rac1, are downstream molecules of PKC-α
in the mTORC2 signaling pathway that regulates actin cytoskeleton.
3.3.2.3. Serum- and Glucocorticoid-induced Protein Kinase 1 (SGK1)
SGK1 is an important substrate of mTORC2. Similar to PKB, following insu-
lin and growth factor stimulation, SGK1 is phosphorylated by PDK1 at its
activation loop on T256 ( Biondi, 2004 ; Mora et al., 2004 ). In order to fully
activate SGK1, mTORC2 is responsible for phosphorylating its S422 residue
at the hydrophobic motif ( Garcia-Martinez and Alessi, 2008 ). More important,
it has been shown that in fibroblasts lacking mTORC2 subunits rictor, Sin1 or
mLST8, the phosphorylation of SGK1 as well as its substrate N-myc down-
stream regulated gene 1 (NDRG1) is abrogated, illustrating the necessity of
the functional mTORC2 in activating SGK1. SGK1 is also a Ser/Thr kinase
that regulates a variety of cellular functions including ion transport, cell pro-
liferation and survival ( Garcia-Martinez and Alessi, 2008 ). Studies have shown
that FoxOs are transcription factors that promote gene transcription involv-
ing in induction of apoptosis and inhibition of cell cycle progression ( Dijkers
et al., 2000a , 2000b ), SGK1 was found to stimulate cell survival and prolifera-
tion by directly phosphorylating FoxO3a to inhibit its nuclear localization
and transcription activity ( Brunet et al., 2001 ; Dehner et al., 2008 ). Moreover,
given the fact that p53 is able to trigger apoptosis ( Soengas et al., 1999 ), SGK1
also enhances cell survival by phosphorylating an E3 ubiquitin ligase Mdm2
(murine double minute, an oncogene) on S166 to promote its binding to p53
for ubiquitination ( Amato et al., 2009 ). Furthermore, mTORC2/SGK1 sig-
naling is required for the expression of another p53 E3 ubiquitin ligase called
human double minute 2 (HDM2). A knockdown of rictor or SGK1 by RNAi