AKT also phosphorylates MDM2, allowing its translocation to the nucleus where it targets p53 for degradation (Zhou and Hung 2002). Moreover, AKT activates inhibitor of nuclear factor (NF) kappa-B kinase (IKK), activating the NF-kB pathway, and resulting in transcription of antiapoptotic genes (Pommier et al. Phosphorylation of the BCL2 Antagonist of Cell Death (BAD) suppresses apoptosis and promotes cell survival (Datta et al. AKT phosphorylates and inhibits Forkhead box O (FOXO) transcription factors, resulting in their degradation in the cytoplasm (Zhang et al. It activates the mammalian target of rapamycin complex 1 (mTORC1), which results in increased protein synthesis and cell survival (Aoki et al. When activated, AKT impacts many cellular processes. Position of pThr308 and pSer473 are indicated (Manning and Toker 2017, Kitagishi et al. 1999) and pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) (Brognard et al. AKT activity is inhibited by dephosphorylation by phosphatases including protein phosphatase type 2A (PP2A) (Millward et al. 2005, Laplante and Sabatini 2012) (Figure 1). Thr308 phosphorylation is mediated by phosphoinositide-dependent kinase-1 ( PDK1) (Vanhaesebroeck and Alessi 2000), whereas Ser473 is phosphorylated by the mammalian target of rapamycin complex 2 (mTORC2) (Sarbassov et al. Phosphorylation of Thr308 and Ser473 are required for full activation of AKT1. In mammals, there are three AKT isoforms ( AKT1, AKT2, and AKT3). AKT has a PH domain at the N-terminus which is required for the binding of PIP3 (Bhaskar and Hay 2007) (Figure 1). The tumor suppressor PTEN is a major negative regulator of the pathway by dephoshorylating the 3’phosphate of PIP3 (Sulis and Parsons 2003). Extracellular signals activate PI3K to generate phosphatidylinositol 3′ phosphate (PIP3). The serine/threonine kinase AKT is a downstream effector of phosphatidylinositol 3-OH kinase (PI3K) (Burgering and Coffer 1995). The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway controls apoptosis, cell proliferation, and the cell cycle (Rodon et al.
0 kommentar(er)
