In our H Ends, AKT phosphorylation Transportation is sometimes in MCF-7 cells after l Through prolonged culture in vitro detectable, suggesting that differences BMS-790052 Daclatasvir in cell culture conditions k Can on the planes p AKT in some cases F. Other studies PIK3CA mutant cell lines of breast cancer generally have more sensitive than PIK3CA c lines Lon mutant cancer cells small molecule AKT inhibition found, suggesting that the effects of the cell line can modulate the pharmacological sensitivity. Overall, these results support the idea that a high Ma AKT AKT p denote a dependence dependence mutated PIK3CA in cancer cells, w While there, the M possibility of signaling AKT independent in contexts in which the station re AKT reduces p. Both before activation and PTEN function modes important regulatory PI3K in cancer therapy.
Interestingly, several cell lines, PIK3CA mutant breast cancer at high AMG 900 p AKT were shown here previously are harboring ERBB2 overexpression / amplification or high activated EGFR. In addition, PIK3CA mutant cells and human breast tumors with low p-AKT with wild-type PTEN and 3 reduced phoshpatidylinositides express w While PTEN knockdown results in AKT phosphorylation tend robust. So many PIK3CA mutant tumors nts on AKT signaling h Contain before simultaneous deregulation of the signal or PTEN deficiency. However PIK3CA mutation by itself ndigen neither necessary nor sufficient for the activation of AKT vervollst pathway, if it i. PIK3CA mutated cells exhibit robust p PDK1 expression and membrane recruitment independently Ngig of AKT signaling.
PDK1 is a constitutively active conformation which is not known to be further verst RKT By upstream signals. PDK1 membrane recruitment oncogenic seems at least partly dependent Ngig of mutant PIK3CA. Membrane localization of PDK1 differential against AKT may partly th different affinity Refer phosphatidylinositide binding PH-Dom Ne, because previous studies suggest that PDK1 may ? 0 times h Here affinity t PIP3 for AKT. K PDK1 recruitment Nnte Also by a function mutant PIK3CA kinase independent Facilitated-dependent, as the stabilization of a complex RTK adapter protein that ortsunabh Phosphatidylinositol-dependent membrane PDK1 erm glicht. for this purpose has been shown PDK1 to the adapter protein independently in a PH-Dom GRB14 ne bind-dependent manner.
W So while the AKT membrane localization hangs fa Be criticized on PIP2 and PIP3 levels high PDK1 localization may require a lower phosphatidylinositide enrichment. PIK3CA mutant cancer cells with low Akt signaling have a dependence Dependence of SGK3 selective for sustainability. SGK family kinases AGC share over 50% identity t With the kinase Dom ne of AKT. SGK proteins Become direct PDK1 substrates after the C-terminal phosphorylation of the hydrophobic motif. Current data suggest that phosphorylation at the HM SGK by TORC2 complex, mediated and SGK proteins Function can k As essential mediators of cell growth behind rictor/TORC2. accordance with previous results, here we show that PDK1 dependent ngig SGK3 PI3K activation in PIK3CA mutant cancer cells is regulated.