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 317

activity ( Guertin et al., 2006 ). However, the necessity for mLST8 in activating
mTORC1 signaling remains unclear. The binding of mLST8 to mTORC1
was shown to stimulate mTORC1's kinase activity toward S6K1 and 4E-BP1
( Kim et al., 2003 ). However, in mLST8-deficient fibroblasts, the association
between mTOR and raptor, as well as the phosphorylation of substrates of
mTORC1 are not impaired, indicating mLST8 has limited function for
mTORC1 in fibroblasts ( Guertin et al., 2006 ). Thus, it is of interest to deter-
mine whether there are mLST8-like protein(s) to rescue the function of
mTORC1 in mLST8-deficient fibroblasts ( Guertin et al., 2006 ). PRAS40
is another negative regulator of mTORC1 ( Oshiro et al., 2007 ; Wang et al.,
2007 ). PRAS40 inhibits mTORC1 activity by binding to mTORC1 via
raptor, and phosphorylation of PRAS40 by PKB leads to its detachment from
mTORC1, activating the complex ( Wang et al., 2008 ). When mTORC1 is
activated by appropriate signals, mTORC1 induces cell growth and prolif-
eration via up-regulation of protein synthesis by phosphorylating S6 protein
kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein
1 (4E-BP1) ( Dazert and Hall, 2011 ; Laplante and Sabatini, 2012 ).
3.2.1. Upstream Signaling Molecules of mTORC1
As noted above, the activity of mTORC1 is modulated by stimuli such as growth
factors, mitogens, amino acids and energy status ( Fig. 6.3 ). For the growth fac-
tors that trigger mTORC1 signaling, insulin is among the best studied ( Mag-
nuson et al., 2012 ; Zoncu et al., 2011 ). Upon binding of insulin or insulin-like
growth factor (IGF) to its receptors, autophosphorylation of these receptors
takes place, which then phosphorylates the insulin receptor substrates (IRS).
Activated IRS in turn phosphorylates PI3K, which catalyzes the conversion
of phosphatidylinositol (4, 5)-bisphosphate (PIP 2 ) to phosphatidylinositol-3, 4,
5-triphosphate (PIP 3 ). This conversion can be reversed by phosphatases and
tensin homolog on chromosome 10 (PTEN), which is an important negative
regulator of mTORC1 pathway by converting PIP 3 to PIP 2 , thus dysregula-
tion of PTEN is detected in numerous kinds of cancer ( Song et al., 2012 ). PIP 3
recruits 3-phosphoinositide-dependent kinase 1 (PDK1) to phosphorylate PKB
on T308 and for full activation, PKB is then phosphorylated by another kinase
on S473 ( Alessi et al., 1997 ; Andjelkovic et al., 1997 ) ( Fig. 6.3 ). Activated PKB
phosphorylates and inhibits tuberous sclerosis complex 2 (TSC2), which asso-
ciates with TSC1 to form a complex that inhibits mTORC1 ( Manning et al.,
2002 ). As GTP-bound Ras-homolog enrich in brain (Rheb) is required for the
activation of mTORC1, the inhibitory effect of TSC1/2 complex is mediated
via its GTPase activity that acts on Rheb to maintain Rheb in a GDP-bound