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was observed, suggesting mTORC2 signaling is necessary for podocytes to
cope with stress conditions and both mTOR complexes work synergistically
together to maintain the integrity of the filtration barrier in the kidney.
It was known that induction of mTORC1 activity by simultaneous deletion
of PTEN and Lkb1, two negative upstream regulators of mTORC1 ( Fig. 6.3 ),
in mouse bladder epithelial cells led to a loss of AJ protein E-cadherin and TJ
adaptor ZO-1, leading to tumor progression ( Shorning et al., 2011 ). Moreover,
it was reported that a knockdown of rictor by RNAi in glioma cells led to
induction of matrix metalloproteinase-9 (MMP-9) mediated by activation of
Raf-1-MEK-ERK pathway, and such activation was caused by the removal
of the inhibitory effect from PKB due to a loss of mTORC2 function. Since
MMP-9 is responsible for breaking down extracellular matrix via its action
on collagen IV, its induction thus contributes to an increase in invasiveness of
glioma tumor cells ( Das et al., 2011 ). In addition, it was shown that in cultured
Sertoli cells, an induction of MMP-9, such as byTNFα, that led to a disruption
of the TJ barrier was mediated via a downregulation of TJ protein occludin
( Siu et al., 2003 ). Collectively, these findings suggest that in Sertoli cells, sup-
pression of mTORC2 activity may result in an MMP-9-mediated disruption
of the BTB. In fact, a recent study has shown that a reduced mTORC2 activity
perturbs the Sertoli BTB function ( Mok et al., 2012a ), whereas a reduced
mTORC1 signaling function promotes the Sertoli TJ-permeability barrier
( Mok et al., 2012c ). These findings thus suggest that these two mTOR com-
plexes work antagonistically to modulate BTB dynamics in the testis.
4. REGULATION OF BTB DYNAMICS BY mTOR
4.1. Background
The involvement of mTOR in BTB dynamics during spermatogenesis has
not been explored until recently ( Mok et al., 2012a ; Mok et al., 2012c ).
As shown in Fig. 6.4 , both mTOR and the crucial subunits that create
mTORC1 (e.g. raptor) and mTORC2 (e.g. rictor) were localized in the
seminiferous epithelium near the basement membrane, consistent with
their localization at the BTB. However, it is noted that the stage-specific
expression of raptor and rictor during the epithelial cycle is different, with
raptor being the highest, but rictor at its lowest, at stage IX of the epithelial
cycle ( Fig. 6.4 ), implicating the mTORC1 and mTORC2 may have dif-
ferential effects on the BTB. These recent findings ( Mok et al., 2012a ; Mok
et al., 2012c ) ( Fig. 6.4 ) coupled with results of other studies in the field
thus support a novel concept depicted in Fig. 6.5 regarding the “yin” and
 
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