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 331

was determined in such a short interval (within 10 min) after adding rapamy-
cin, the actin reorganization should be attributed to a loss of TOR1 function
only since mTORC2 remained unaffected during this short period of time
( Aronova et al., 2007 ). Second, in Rh30 and dU-373 mammalian cancer cell
lines, treatment of these cells with rapamycin for 2 h was found to inhibit
the type I insulin-like growth factor (IGF-I)-stimulated F-actin reorganization,
confirming the involvement of mTORC1 signaling in actin dynamics ( Liu
et al., 2008 ). Also, in ovarian cancer cells transfected with constitutively active
S6K1, actin reorganization to facilitate the formation of actin-based lamellipo-
dia, actin microspikes and filopodia were induced in these cells, and such actin
cytoskeleton restructuring was mediated via Rac1 and Cdc42 ( Ip et al., 2011 ).
Furthermore, phosphorylated S6K1 was found to bind to F-actin, cross-linking
actin filaments, thereby stabilizing F-actin as it significantly reduced the rate and
extent of actin filament depolymerization induced by cofilin ( Ip et al., 2011 ). In
short, these recent findings illustrate that although mTORC1 and mTORC2
possess distinctive substrates and different downstream signaling molecules, they
both regulate cell proliferation and F-actin organization in cells.
3.5. Regulation of Blood-Tissue Barrier Function by mTOR
3.5.1. Regulation of Barrier Function in The Kidney by mTOR
Among the numerous cellular processes mediated by mTOR, its effects on
immune response in mammals are well characterized. Rapamycin, a potent
inhibitor of mTOR, is an immunosuppressant drug widely used by kidney
and heart transplant patients ( Diekmann and Campistol, 2006 ; Kahan, 2001 ).
However, after prolonged exposure to rapamycin, proteinuria (a pathological
condition with excessive serum proteins found in urine) and even nephritic
syndrome were observed in some patients ( Aliabadi et al., 2008 ; Dittrich et al.,
2004 ; Izzedine et al., 2005 ; van den Akker et al., 2006 ). Such pathological con-
dition was later found to be the result of damages in podocytes, which are the
cells responsible for maintaining the blood-urine filtration barrier of the renal
glomerulus in the kidney. This selective barrier is created via a unique cell-
cell contact called the slit diaphragm established by primary and secondary
foot processes from podocytes ( Paventadt et al., 2003 ). In cultured human
immortal podocytes, prolonged treatment of rapamycin downregulated
mTOR and rictor and thus reduced the formation of mTORC2, leading to
reduced phosphorylation of PKB on S473 ( Vollenbroker et al., 2009 ). The
suppression of mTORC2 signaling disrupted the podocyte-based filtration
barrier, which was the result of reduced cell adhesion. Such reduction of cell
adhesion was mediated, at least in part, by a loss of slit diaphragm proteins,