Phosphorylation of AKT: a Mutational Analysis

Abstract

Akt (cellular homolog of murine thymoma virus akt8 oncogene) is an essential component of the PI3K (phosphatidylinositol 3-kinase) pathway. Its activity is stimulated by receptor tyrosine kinases and G-protein coupled receptors and plays a critical role in the regulation of cell proliferation, differentiation and apoptosis. A gain of function in Akt can lead to uncontrolled cell proliferation and resistance to apoptosis, both hallmarks of oncogenic transformation. In this communication, we have investigated the phosphorylation at the Akt residues T308, S473 and T450 and their roles in oncogenic transformation and signaling. We find that T450 phosphorylation has only a minimal part in these activities. In contrast, the phosphorylation of T308 and of S473 fulfills essential, distinct, and non-overlapping functions that we define with inactivating and with phosphomimetic mutations of these sites.

MDM2 Regulates Hypoxic Hypoxia-inducible Factor 1α Stability in an E3 Ligase, Proteasome, and PTEN-Phosphatidylinositol 3-Kinase-AKT-dependent Manner

“…3F). This observation is consistent with the literature, which has reported that Myr-AKT, although membrane-localized, requires phosphatidylinositol 1,4,5-trisphosphate-dependent phosphorylation on Thr 308 by PDK1 for full activation (48).…”

Mammalian Target of Rapamycin Complex 1 (mTORC1) and 2 (mTORC2) Control the Dendritic Arbor Morphology of Hippocampal Neurons

“…Nevertheless, the myr-Akt mutant was shown to effectively reverse the effects of even full Rictor depletion (50 -52). Moreover, when the myrAkt mutant was compared in experiments with phospho-mimicking non-myristoylated Akt mutants, their ability to rescue the phenotypic effects of Rictor knock-out was similar (48). Another potential explanation for mTORC2-independent activation of myr-Akt was provided by work of Warfel et al (39).…”

“…One possibility is that membrane targeting caused by a myristoylation signal overrides the need for Ser-473 phosphorylation. No full consensus has been reached regarding this issue (48,49). Nevertheless, the myr-Akt mutant was shown to effectively reverse the effects of even full Rictor depletion (50 -52).…”

Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle

“…19,20 Phosphorylation of other residues is important also for Akt folding, stability, and activity. [21][22][23][24][25] Despite a large body of data dealing with the regulation of Akt by phosphorylation, the information about the influence of other PTMs on Akt activity is less abundant. It has been shown that Akt as well as PDK1 activity is regulated by reversible acetylation.…”