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 330

led to downregulation of HDM2, illustrating the significant of mTORC2/
SGK1 pathway for inhibiting p53 to modulate cell survival ( Lyo et al., 2010 ).
Taken collectively, these studies show that besides PKB, mTORC2 can mod-
ulate cell proliferation as well as survival through SGK1. SGK1 is likely to play
a crucial role in carcinogenesis since it is overexpressed in a variety of tumors
( Fagerli et al., 2011 ; Simon et al., 2007 ; Zhang et al., 2005 ) and its suppres-
sion is able to reduce tumor development. For instance, mice lacking SGK1
were found to be more resistant to chemically induced colon cancer ( Nasir
et al., 2009 ). Whereas in adenoma polyposis coli (APC)-deficient mice, which
developed gastrointestinal tumors spontaneously, the lack of SGK1 led to
reduced intestinal tumor development ( Wang et al., 2010 ). However, the role
of SGK1 in spermatogenesis and other testicular function remain unexplored.
Nontheless, these findings illustrate that SGK1 may be involved in regulating
germ cell apoptosis during spermatogenesis.
3.4. The Interplay between mTORC1 and mTORC2
in Regulating Cellular Events
As described above, mTORC1 and mTORC2 have their distinctive down-
stream substrates and signaling molecules so that they regulate distinctive cel-
lular functions. However, these two pathways are also interconnected and can
interact with each other to affect phenotypes. For example, both signaling
complexes are activated upon stimulation by growth factors and amino acids.
Besides, they also share the same upstream regulator, TSC1/2 complex, which
promotes the activity of mTORC1 but suppresses mTORC2 ( Fig. 6.3 ). More
important, S6K1, which is the substrate of mTORC1, can phosphorylate ric-
tor, the critical binding partner of mTORC2, and inhibit the catalytic activity
of mTORC2 on PKB, which is also the upstream regulator of mTORC1,
thereby creating as a negative feedback loop ( Fig. 6.3 ). Besides sharing com-
mon activating stimuli and regulators, recent studies have suggested that some
of the cellular functions modulated by these signaling complexes are indeed
overlapping, despite the fact that they have their specific substrates. For instance,
mTORC1 regulates cell proliferation via S6K1 and rpS6, whereas mTORC2
modulates the same cellular process with PKB and SGK1. Furthermore, regu-
lation of actin cytoskeleton was once regarded as a specific role of mTORC2,
but several recent studies indicate that mTORC1 may be involved in this
event. First, a study performed in yeasts revealed that rapamycin treatment
which inhibited TORC1 signaling was found to perturb actin polarization
within 10 min, and this treatment also delayed actin repolarization after glu-
cose starvation ( Aronova et al., 2007 ). Since significant actin depolarization