Posttranslational regulation of Akt in human cancer

Abstract

Akt regulates critical cellular processes including cell survival and proliferation, glucose metabolism, cell migration, cancer progression and metastasis through phosphorylation of a variety of downstream targets. The Akt pathway is one of the most prevalently hyperactivated signaling pathways in human cancer, thus, research deciphering molecular mechanisms which underlie the aberrant Akt activation has received enormous attention. The PI3K-dependent Akt serine/threonine phosphorylation by PDK1 and mTORC2 has long been thought to be the primary mechanism accounting for Akt activation. However, this regulation alone does not sufficiently explain how Akt hyperactivation can occur in tumors with normal levels of PI3K/PTEN activity. Mounting evidence demonstrates that aberrant Akt activation can be attributed to other posttranslational modifications, which include tyrosine phosphorylation, O-GlcNAcylation, as well as lysine modifications: ubiquitination, SUMOylation and acetylation. Among them, K63-linked ubiquitination has been shown to be a critical step for Akt signal activation by facilitating its membrane recruitment. Deficiency of E3 ligases responsible for growth factor-induced Akt activation leads to tumor suppression. Therefore, a comprehensive understanding of posttranslational modifications in Akt regulation will offer novel strategies for cancer therapy.

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

“…These modifications might be important for additional functions of Akt isoforms in normal cells and for hyperactivation of Akt in tumor cells, even with normal levels of Akt and PTEN [89]. Understanding the network of post-translational modifications of Akt isoforms in tumor cells might help to identify novel targeting approaches for cancer therapy.…”

MicroRNA-195 targets VEGFR2 and has a tumor suppressive role in ACHN cells via PI3K/Akt and Raf/MEK/ERK signaling pathways

“…Thus, we investigated whether VEGFR2 could be regulated by miR-195, which had an inhibitory effect on ACHN cells through PI3K/Akt and Raf/MEK/ERK signaling pathways. We used qRT-PCR and western blot analysis to detect the expression levels of VEGFR-2 and its downstream signal molecules: Akt, MEK and ERK in different groups, tyrosine phosphorylation of these proteins is essential for cancer cell proliferation (26,27). The results indicated miR-195 suppressed the VEGFR2 mRNA, but had no effect on mRNA of MEK, ERK or Akt.…”

The DNA Damage Transducer RNF8 Facilitates Cancer Chemoresistance and Progression through Twist Activation

“…Ubiquitination is a reversible post-translational modification that is essential for regulation of protein stability, function and subcellular localization (Chan et al, 2014; Mattiroli and Sixma, 2014). The versatility of ubiquitination stems from its ability to form topologically different ubiquitin chains.…”