Together, these results biochemical evidence that SGK3 AKT downstream signals independently Ngig gt of PDK1 in PIK3CA mutated cells tr, Although the importance of PDK1 zus Tzlichen substrates and effectors replacement can not be excluded. We then tested wUe SGK3 activity T  in PIK3CA mutant frame. The PX Dom ne SGK3 gives endosomal K Rperregion by his lust for phosphatidylinositide 3-phosphate, which is present in high levels in endosomal membranes. As expected, the expression of SGK3 LY335979 Zosuquidar PX Dom ne fused to GFP localized to endosomes construct examined in all cell lines, this localization was not affected by treatment with LY 294002nd However, LY 294002 significantly reduced dependent PDK1 phosphorylation Ngig SGK3 in PIK3CA mutant cells with low p AKT. Sun SGK3 localization is not regulated endosomal PI3K activation in PIK3CA mutation. Next we have found depends to what Extent these SGK3 Ngig PDK1 phosphorylation in cancer cells and its relationship with PTEN or PIK3CA mutation. Although p SGK3 in transformed cells was not detectable.
This phosphorylation event was in various cancer cell lines, including normal cells most PIK3CAmutant investigated obvious. In addition, only SGK3 and SGK1 or not SGK2 consistently in all relevant sectors PIK3CA mutant cell was expressed in our panel. Taken together, these results suggest that activation may SGK3 a feature of many cancers, independently His ngig of AKT signaling. AM-1241 Aberrant PI3K signaling has been extensively studied in cancer. This study provides evidence that PIK3CA mutations k Able to tumorigenesis through both AKT-dependent Dependent and AKT-independent Help-dependent mechanisms. AKT activation in the absence of PDK1 can transmit an alternating signal downstream the other Rts substrates such as SGK3 PIK3CAmutant acts in cancer cells.
This study calls and both PDK1 and SGK3 the key downstream effectors Rts of oncogenic PIK3CA activating mutations. Our results differ AKT signaling studies in which mutant PIK3CA was ectopically in cell culture models of embryonic / chick immortalized expressly or methods introduced by gunshot in breast epithelial cells. On the other hand, several lines of experimental evidence suggest that station presented here Ren AKT signaling in many contexts where malignant PIK3CA mutations are reduced in situ. In addition, AKT activation patterns and PDK1 we observed in many human cell lines and clinical samples of breast tumors consistent, consistent with published observations. S good R, k We can not completely exclude S that AKT signaling at very low levels in some cancers, PIK3CA mutants operates, even if poorly detectable by herk Mmliche methods.
However, our findings that in some situations the functional performance of different PIK3CA mutations of fa It is important that the PI3 kinase deregulation observed in PTEN 0 cells. Studies with selective inhibitors of small molecules AKT can to plaintiff of the nature of addiction AKT in PIK3CA mutated tumors tion. In line with our results in vitro susceptibility to inhibition by small molecule allosteric AKT1 / 2 inhibitors was strongly correlated with the phosphorylation of Akt in cancer cell lines. Suppressed in the study, et al, p AKT was detectable in MCF7 cells. By an inhibitor of AKT However, MCF-7 cells showed sensitivity to pharmacological attenuated Want AKT1 / 2 with respect to the inhibition of various cancer cell lines significantly increased FITTINGS levels of AKT p.