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 319

status. After the phosphorylation of TSC2, TSC1/2 complex is inhibited and
hence, Rheb-GTP is accumulated for the activation of mTORC1.
In addition to TSC1/2 complex, PKB also promotes mTORC1 signaling
by phosphorylating PRAS40. As such, PRAS40 is dissociated with raptor and
hence, its inhibitory effect is removed ( Wang et al., 2008 ). Moreover, besides
the above PKB-mediated pathways, binding of growth factors or mitogens
to their receptors can also activate mTORC1 via the Ras-Raf-MEK-ERK
signaling. Upon the above activation, the small GTPase Ras eventually leads
to phosphorylation of ERK1 and ERK2, which in turn inhibits the TSC1/2
complex by directly phosphorylating TSC2 or via activation of RSK1 that
also phosphorylates and inhibits TSC2 ( Ma et al., 2005 ; Roux et al., 2004 ).
Furthermore, ERK1/2 and RSK1 also phosphorylate raptor to promote
mTORC1 functions ( Carriere et al., 2008 , 2011 ) (Fig. 6.3). While mTORC1
signaling has to be “on” to upregulate protein synthesis in response to growth
factors and mitogens, there are conditions that mTORC1 pathway has to
be “off,” for example, when cells are in energy stress. When cellular ATP
decreases, the rise of AMP/ATP ratio activates Lkb1 (liver kinase B1, also
known as Ser/Thr kinase 11, STK11) to phosphorylate AMPK ( Shackelford
and Shaw, 2009 ), which in turn phosphorylates raptor, inhibiting mTORC1
as mentioned above ( Gwinn et al., 2008 ). Besides, AMPK phosphorylates and
activates TSC2, thus mTORC1 is suppressed by the TSC1/2 activity which
catalyzes the conversion of Rheb-GTP to Rheb-GDP ( Inoki et al., 2003 ).
3.2.2. Downstream Signaling Molecules of mTORC1
3.2.2.1. S6 Protein Kinases
Upon activation, mTORC1 up-regulates protein synthesis mainly through
its two substrates S6K and 4E-BP1. In mammals, S6K is a family of protein
mTORC2. Besides mTORC1 that is specifically regulated by the energy status of a cell,
both mTOR complexes are activated by growth factors (e.g. insulin), mitogens and amino
acids. Upon activation, except that upregulation of protein synthesis for cell growth is
specifically mediated by mTORC1, the control of cell proliferation and survival as well
as actin cytoskeleton organization is modulated by both complexes, despite the fact
that they have their unique substrates and downstream signaling molecules. Moreover,
mTORC1 and mTORC2 share several upstream signaling molecules. For example, PIP 3 can
activate both complexes while TSC1/2 complex inhibits mTORC1 but activates mTORC2.
Furthermore, the signaling pathways of the two mTOR complexes are interconnected in
which S6K1, the substrate of mTORC1, is able to phosphorylate rictor and thus inhibits
mTORC2. As such, phosphorylation of PKB, which is the substrate of mTORC2, can be
reduced. Since PKB phosphorylation is required for activating mTORC1, this leads to sup-
pression of mTORC1 signaling and therefore, a negative feedback loop is established. For
color version of this igure, the reader is referred to the online version of this topic.