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 316

FKBP12-rapamycin complex does not bind to mTORC2 ( Oh and Jacinto,
2011 ; Zhou and Huang, 2010 ). The key binding partner of mTORC2 is
rictor (rapamycin-insensitive companion of mTOR). Unlike mTORC1,
mTORC2 regulates actin cytoskeleton and cell survival. Besides rictor,
other subunits of mTORC2 include Sin1, mLST8, deptor, Hsp70 and pro-
tor-1/2. Interestingly, subsequent studies have shown that while mTORC2
is insensitive to rapamycin, but this is limited to short-term exposure since
prolonged rapamycin challenge at up to 24 h leads to the dissociation of
rictor from mTOR, disabling the mTORC2 signaling ( Sarbassov et al.,
2006 ). Although FKBP12-rapamycin complex does not bind to mTORC2,
it was proposed that after long-term treatment, the availability of mTOR
decreased as newly synthesized mTOR was occupied by FKBP12-rapa-
mycin complex, preventing the formation of mTORC2. Different binding
partners among mTORC1 and mTORC2 allow these kinases responding
to different stimulating signals so that they can phosphorylate unique sets
of substrates to induce distinctive physiological responses.
3.2. Mammalian Target of Rapamycin Complex 1 (mTORC1)
mTORC1 is composed of mTOR, raptor, proline-rich Akt/PKB substrate
40 kDa (PRAS40), mTOR associated protein LST8 homolog (mLST8)
and DEP domain-containing mTOR-interacting protein (deptor) (Fig.
6.3). Among them, raptor is the key binding partner which acts as a criti-
cal scaffolding protein that controls mTORC1 assembly and the selection
of substrates ( Kim et al., 2002 ; Nojima et al., 2003 ; Schalm et al., 2003 ).
In the absence of nutrients, raptor associates with mTOR stably to repress
mTORC1 catalytic activity while under nutrient-rich conditions, the bind-
ing of raptor to mTOR is unstable but this unstable mTOR-raptor associa-
tion is necessary for mTORC1 to carry out its kinase activity ( Kim et al.,
2002 ). Raptor can be phosphorylated at multiple sites for either up- or
down-regulating mTORC1 activity ( Zhou and Huang, 2010 ). For instance,
under energy stress conditions, AMP-activated protein kinase (AMPK)
phosphorylates raptor on S722 and S792 to induce binding of 14-3-3
protein to mTORC1 to elicit its inhibition, leading to cell cycle arrest
( Gwinn et al., 2008 ). Activation of mTORC1 by mitogens, however, is medi-
ated via phosphorylation of raptor on S719, S721 and S722 by p90 ribosomal
S6 kinases (RSKs) ( Carriere et al., 2008 ). Deptor (an inhibitor of mTOR)
and mLST8 are common subunits among mTORC1 and mTORC2. Dep-
tor binds to both mTOR complexes and functions as a negative regulator
( Peterson et al., 2009 ). For mLST8, it is required for mTORC2 to maintain its