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kinase domains, and shared common structural features. For example, there is an
activation loop in the catalytic domain of these molecules, and its phosphoryla-
tion leads to conformational changes which are essential to elicit the intrinsic
catalytic activity of the enzyme (
Parker and Parkinson, 2001
;
Pearce et al., 2010
).
Many AGC kinases also contain a hydrophobic motif located behind the kinase
domain, and phosphorylation of this motif is required for stabilizing their active
conformation. In addition, several AGC kinases have a turn motif (
Parker and
Parkinson, 2001
;
Pearce et al., 2010
), which is an important phosphorylation
site that promotes the integrity of the enzyme as well as maintaining its confor-
mation for full kinase activity (
Parker and Parkinson, 2001
;
Pearce et al., 2010
).
3.3.2.1. Protein Kinase B
Among the substrates of mTORC2, PKB is the best characterized, which is
known to be involved in regulating numerous cellular aspects including pro-
liferation, survival, protein synthesis and metabolism. As mentioned previously,
PIP
3
produced upon growth factor stimulation is responsible for recruiting
PKB to the plasma membrane, where it is phosphorylated by PDK1 at its
activation loop on T308 (
Alessi et al., 1997
;
Andjelkovic et al., 1997
). In order
for PKB to perform its kinase activity, it has to be further phosphorylated on
S473 at the hydrophobic motif by mTORC2, and this phosphorylation is
essential for PKB activation (
Sarbassov et al., 2005
). Furthermore, mTORC2 is
also responsible for phosphorylating PKB on T450 at the turn motif (
Oh et al.,
2010
). In short, mTORC2 phosphorylates PKB on S473 and T450 to elicit its
full activation, and hence, PKB can effectively stimulate its substrates to regulate
numerous cellular functions. For instance, FoxOs (transcription factors of the
Forkhead box O class) are a family of transcription factors which promote the
transcription of cell cycle inhibitors, and factors that induce apoptosis (
Dijkers
et al., 2000a
,
2000b
). Upon their phosphorylation by PKB, FoxOs are inhibited
and hence, cell proliferation and survival are enhanced (
Kloet and Burger-
ing, 2011
). Moreover, PKB also promotes cell survival with the aid of 14-3-3
protein. When exposed to survival factors, PKB phosphorylates BAD, a pro-
apoptotic Bcl-2 family protein, on S136 and this phosphorylation leads to the
association of 14-3-3 protein with BAD. As such, the accessibility of kinases, like
PKB, to phosphorylate BAD on S155 is greatly enhanced and such phosphor-
ylation inhibits BAD from interacting with prosurvival Bcl-2 family members
to induce apoptosis (
Datta et al., 1997
,
2000
). PKB also upregulates protein
synthesis by phosphorylating and inhibiting TSC2 and PRAS40, leading to the
activation of mTORC1 signaling that enhances protein synthesis via S6K1 and
4E-BP1. Furthermore, PKB also modulates the activity of enzymes involved in
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