Physiological regulation of Akt activity and stability

Abstract

The serine/threonine protein kinase B (PKB, also known as Akt) constitutes an important node in diverse signaling cascades downstream of growth factor receptor tyrosine kinases. Akt plays an essential role in cell survival, growth, migration, proliferation, polarity, and metabolism (lipid and glucose); cell cycle progression; muscle and cardiomyocyte contractility; angiogenesis; and self-renewal of stem cells. Altered Akt activity has been associated with cancer and other disease conditions, such as diabetes mellitus, neurodegenerative diseases, and muscle hypotrophy. In the past decade, the upstream signals that lead to Akt activation, the downstream substrates that exert the effects of Akt, and the secondary binding proteins that regulate Akt activation have been well documented. Recent reports from our group and others have revealed how the stability of Akt protein is regulated through phosphorylation on its Thr-Pro motifs. This literature review details findings of those reports and others relevant to the regulation of Akt activation by its upstream kinases, with a focus on mammalian target of rapamycin complexes (mTORCs) and inactivation by PHLDA3 and the protein phosphatases PP2A and pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP). Reports on ubiquitin-dependent Akt degradation, caspase-dependent cleavage, and the roles of molecular chaperone heat shock protein 90 (Hsp90) in the regulation of Akt stability are summarized. The highlight will be on the role of "turn motif" phosphorylation and an isomerase, Pin1, in the regulation of Akt stability. We also discuss issues related to the intricate mTORC2-AktmTORC1 loop and the contradictory regulation of Akt phosphorylation and stabilization of Akt by mTORC2. Finally, we offer perspective on potential future directions for investigation, particularly on translating the knowledge we learned on the regulation of Akt stability into therapeutic intervention on human cancer with Akt alteration.

Keywords: Akt; DEPTOR; PH domain; PHLDAs; PHLPPs; PKB; PP2A; Pin1; Serine/threonine protein kinase B; caspase; growth factor receptor; heat shock protein; mTORCs; mammalian target of rapamycin complexes; physiological activity regulation; pleckstrin homology domain; stability; tyrosine kinases.

Figure 1

Akt domains and comparison of Akt isoforms (% of homology). Chromosome location of each Akt isoform in human as well as reported phosphorylation sites in Akt1 are also depicted. Color-embedded sites are the major focus of the current review.

Figure 2

Cellular signaling around Akt and Akt substrates regulated major cellular processes.

Figure 3

The PTEN-PI3K-Akt-p53-PHLDA3 feedback loop.

Figure 4

A plausible model on Pin1-mediated regulation of Akt stability and activation phosphorylation.