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the assembly of mTORC2 to regulate development (
Guertin et al., 2006
).
Additionally, rictor has up to 37 phosphorylation sites with most of them
are located at its C-terminus (
Dibble et al., 2009
). Activity of the mTORC2
can be regulated via these phosphorylation sites in response to different
stimuli. For example, phosphorylation of T1135, which is sensitive to amino
acid and growth factors, leads to reduced phosphorylation of PKB (
Dibble
et al., 2009
;
Julien et al., 2010
). Another mTORC2 exclusive subunit that
is essential for the stability of whole complex is Sin1 since a knockdown
of Sin1 was found to disrupt the interaction between mTOR and rictor,
reducing PKB phosphorylation (
Yang et al., 2006
). Additionally, Sin1 may
be able to modulate the activity of mTORC2 through the phosphorylation
status of rictor since following a knockdown of Sin1, phosphorylation of
rictor was reduced (
Yang et al., 2006
). Moreover, it is of interest to know
that five Sin1 isoforms are generated through alternative splicing, and at least
three distinctive mTORC2 complexes can be formed by three of the Sin1
isoforms, each of which may have unique but yet-to-be identified func-
tions (
Frias et al., 2006
). Hsp70 is another mTORC2-specific subunit that
is required for the association between mTOR and rictor. It was shown that
after knockdown of Hsp70, binding between mTOR and rictor, but not
raptor, was disrupted (
Martin et al., 2008
). Besides, only the phosphorylation
of PKB, but not S6K1, was reduced after knockdown of Hsp70, indicating
Hsp70 is indispensable for mTORC2, but not mTORC1 function (
Martin
et al., 2008
). For Protor-1/2, although it is a subunit of mTORC2, the loss
of Protor-1, but not Protor-2, led to reduced phosphorylation of SGK1, but
not PKB and PKC-α, revealing Protor-1 may be needed by mTORC2 to
activate SGK1 efficiently (
Pearce et al., 2011
).
3.3.1. Upstream Signaling Molecules of mTORC2
mTORC2 was first identified as a protein Ser/Thr kinase that phosphory-
lated PKB specifically on S473, which was stimulated by growth factors after
serum depletion (
Sarbassov et al., 2005
). Subsequent study has demonstrated
that besides PKB, SGK1 is another substrate of mTORC2 (
Garcia-Martinez
and Alessi, 2008
). Since growth factors are known to (i) activate SGK1 and
mTORC2 and (ii) generate PIP
3
by PI3K, it was believed that PIP
3
was able
to stimulate mTORC2 for activating SGK1 via an unknown mechanism(s).
It is now known that PIP
3
can directly bind to and activate mTORC2 that
leads to the phosphorylation of PKB and PKC-α by mTORC2 (
Gan et al.,
2011
). Besides growth factors, mTORC2 can also be regulated by amino
acids. After serum starvation, addition of Leu to HeLa cells is able to induce
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