Gastrointestinal tumors spontaneously, the lack of SGK1 led to lowered intestinal tumor development (Wang et al., 2010). Nevertheless, the role of SGK1 in spermatogenesis and otherViral Proteins Biological Activity NIH-PA Author GM-CSF Proteins medchemexpress manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptInt Rev Cell Mol Biol. Author manuscript; offered in PMC 2014 July 08.Mok et al.Pagetesticular function stay unexplored. Nontheless, these findings illustrate that SGK1 may very well be involved in regulating germ cell apoptosis in the course of spermatogenesis.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript3.4. The Interplay between mTORC1 and mTORC2 in Regulating Cellular Events As described above, mTORC1 and mTORC2 have their distinctive downstream substrates and signaling molecules so that they regulate distinctive cellular functions. Even so, these two pathways are also interconnected and may interact with one another to affect phenotypes. For example, both signaling complexes are activated upon stimulation by growth factors and amino acids. Apart from, in addition they share the same upstream regulator, TSC1/2 complex, which promotes the activity of mTORC1 but suppresses mTORC2 (Fig. six.three). Much more important, S6K1, which is the substrate of mTORC1, can phosphorylate rictor, the important binding partner of mTORC2, and inhibit the catalytic activity of mTORC2 on PKB, which can be also the upstream regulator of mTORC1, thereby generating as a damaging feedback loop (Fig. 6.three). In addition to sharing common activating stimuli and regulators, current studies have suggested that some of the cellular functions modulated by these signaling complexes are indeed overlapping, in spite of the truth that they have their certain substrates. As an illustration, mTORC1 regulates cell proliferation by way of S6K1 and rpS6, whereas mTORC2 modulates precisely the same cellular procedure with PKB and SGK1. Additionally, regulation of actin cytoskeleton was once regarded as a particular role of mTORC2, but several current studies indicate that mTORC1 might be involved within this event. Very first, a study performed in yeasts revealed that rapamycin remedy which inhibited TORC1 signaling was identified to perturb actin polarization inside 10 min, and this treatment also delayed actin repolarization soon after glucose starvation (Aronova et al., 2007). Considering that important actin depolarization was determined in such a short interval (inside 10 min) immediately after adding rapamycin, the actin reorganization needs to be attributed to a loss of TOR1 function only considering that mTORC2 remained unaffected through this short time frame (Aronova et al., 2007). Second, in Rh30 and dU-373 mammalian cancer cell lines, therapy of these cells with rapamycin for 2 h was discovered to inhibit the sort 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 lamellipodia, actin microspikes and filopodia were induced in these cells, and such actin cytoskeleton restructuring was mediated through Rac1 and Cdc42 (Ip et al., 2011). Moreover, phosphorylated S6K1 was located to bind to F-actin, cross-linking actin filaments, thereby stabilizing F-actin as it considerably decreased the rate and extent of actin filament depolymerization induced by cofilin (Ip et al., 2011). In quick, these recent findings illustrate that while mTORC1 and mTORC2 possess distinctive substrates and differe.
