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 326

mTORC2-dependent cell migration via actin-reorganization mediated by
Rac ( Hernandez-Negrete et al., 2007 ). Amino acids also induced phosphory-
lation of PKB on S473 by mTORC2 and such phosphorylation was per-
turbed by a knockdown of rictor ( Tato et al., 2011 ). Other than growth
factors and amino acids, mTORC1 and mTORC2 also share other com-
mon upstream stimuli/signaling molecules. It has been demonstrated that
TSC1/2 complex, an inhibitor of mTORC1, can be physically associated
with mTOR2. However, in contrast to its inhibitory effect on mTORC1,
TSC1/2 complex binds and activates mTORC2 in a manner independent
of its GTPase-activating protein activity ( Huang et al., 2008 ) ( Fig. 6.3 ). It
was shown that a loss of TSC1/2 complex led to impaired phosphoryla-
tion of all the known downstream effectors of mTORC2 including PKB,
PKC-α and SGK1, thus confirming the necessity of TSC1/2 complex in
mTORC2 activation ( Huang et al., 2009 ). In addition to TSC1/2 complex,
PTEN, which is also a suppressor of mTORC1, seems to exert its effect
upstream of mTORC2 ( Fig. 6.3 ). Among the upstream signaling molecules
of mTORC2, perhaps the most interesting is S6K1, which is also a substrate
of mTORC1. Growth factors are known to induce phosphorylation of rictor
at T1135, which is directly mediated by S6K1 in a rapamycin-sensitive man-
ner ( Dibble et al., 2009 ; Julien et al., 2010 ; Treins et al., 2010 ). Although such
phosphorylation does not affect mTORC2 integrity, intrinsic kinase activity
or cellular localization, it triggers the binding of rictor to 14-3-3 proteins,
which is a family of regulatory molecules that modulate numerous cellular
events including spermatogenesis in the testis ( Hermeking, 2003 ; Sun et al.,
2009 ). In addition, overexpression of rictor with nonphosphorylatable T1135
in wild-type or rictor-null cells led to an increase of PKB phosphorylation
on S473 while the phosphorylation status of PKC-α and SGK1 remained
unchanged, indicating phosphorylation of rictor by S6K1 may indeed nega-
tively regulate the activation of PKB by mTORC2. The findings summarized
herein illustrate mTORC1 and mTORC2 form a connected signaling net-
work that the two signaling complexes interact with each other functionally
( Fig. 6.3 ). For instance, as PKB is needed for stimulating mTORC1, the sup-
pression of mTORC2 on PKB activation by the mTORC1 substrate S6K1
may act as a negative feedback system to prevent overactivation of mTORC1.
3.3.2. Downstream Signaling Molecules of mTORC2
PKB, PKC-α and SGK1 are the three known downstream effectors of
mTORC2 and they are members of the AGC kinase (PKA, PKG, PKC) family
( Fig. 6.3 ). AGC kinases have highly conserved primary sequence within their