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 321

phosphorylating SKAR on S383 and S385 ( Richardson et al., 2004 ). It is of
interest to point out that SKAR was shown to be specifically phosphorylated
by S6K1, but not S6K2, in regulating cell size ( Richardson et al., 2004 ).
Besides regulating cell growth, S6K is also involved in stimulating cell
proliferation. Rapamycin treatment has been shown to arrest cell cycle in
mammalian lymphocytes at G 1 phase; however, rapamycin treatment only
delays cell cycle progression in other mammalian cell types ( Abraham and
Wiederrecht, 1996 ). This indicates the significance of mTORC1 signaling
in cell cycle progression and S6K is one of the mediators since G 1 phase
progression was shown to be accelerated by overexpression of constitutively
active S6K1 ( Fingar et al., 2004 ). On the other hand, the importance of
S6K2 in cell proliferation is illustrated in study demonstrating S6K2 was
responsible for the interleukin-3 (IL-3)-driven cell proliferation since S6K2
was activated in lymphocytes and primary mouse bone marrow-derived
mast cells upon IL-3 induced proliferation; and cell cycle progression was
accelerated by overexpression of constitutively active S6K2 in lymphocytes
( Cruz et al., 2005 ). Furthermore, the association of heterogeneous ribonu-
cleoprotein (hnRNP) F with mTOR and S6K2, but not S6K1, is essential
for driving cell proliferation ( Goh et al., 2010 ). Taking collectively, both
S6K1 and S6K2 are involved in mTORC1-mediated cell cycle progression.
Interestingly, S6K1 is predominantly found in the cell cytosol versus S6K2
in the cell nucleus ( Lee-Fruman et al., 1999 ).
3.2.2.2. Ribosomal Protein S6 (rpS6)
rpS6 was the first S6K substrate identified, and was thought to be its effector
to upregulated protein synthesis ( Magnuson et al., 2012 ). rpS6 is one of the
ribosomal proteins of the 40S subunit of eukaryotic ribosomes ( Wool, 1996 ).
Much attention was given to rpS6 in the past since it was shown to undergo
inducible phosphorylation upon a wide range of stimuli that upregulated
protein synthesis ( Gressner and Wool, 1974 ; Thomas et al., 1982 ; Wettenhall
and Howlett, 1979 ; Wool, 1979 ). rpS6 can be phosphorylated in five residues
located at the C-terminus: S235, S236, S240, S244 and S247 ( Bandi et al.,
1993 ; Krieq et al., 1988 ). It was suggested that phosphorylation progressed
in an orderly manner that S236 is the primary phosphorylation site ( Flotow
and Thomas, 1992 ; Wettenhall et al., 1992 ). Full phosphorylation of rpS6
requires the presence of both S6K isoforms with S6K2 being the predomi-
nant kinase. However, studies reported in cells lacking both S6K or after
rapamycin treatment wherein S6K activation was completely abolished, yet
rpS6 was still being phosphorylated on S235 and S236. This thus illustrates