The critical role of Akt in cardiovascular function

Abstract

Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1. Translocation of Akt to the cell membrane facilitates PDK1 phosphorylation of the threonine site. The serine site is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKKε are some of the non-canonical pathways which affect the Akt activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to other proteins such as CTMP and TRB3 reduces the Akt activity. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism. Akt promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities. Inhibition of FoxO proteins by Akt also increases cell survival by transcriptional mechanisms. Akt stimulates cell growth and proliferation through mTORC1. Akt also increases VEGF secretion and mediates eNOS phosphorylation, vasorelaxation and angiogenesis. Akt can increase cellular metabolism through its downstream targets GSK3 and GLUT4. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases.

Keywords: Akt; Signal transduction; Vascular remodeling.

Figure 1

Human Akt protein structure. Akt has a characteristic pleckstrin homology (PH) domain at the amino terminal (~ 110 amino acids), a middle kinase domain (~260 amino acids) and a carboxy-terminal regulatory domain (~70 amino acids).

Figure 2

The upstream signals of Akt. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. beta-catenin/Tcf-4, GLI1 and Stat-3 are known transcriptional regulators of AKT gene. T308 and S473 are the two critical phosphorylation sites of Akt1. Affinity of Akt to PtdIns (3,4,5) P3 is required for membrane translocation. PI3 kinase-dependent phosphorylation of T308 is through PDK1. S473 is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKKε are some of the non-canonical pathways which affect the Akt activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to CTMP and TRB3 reduces the Akt activity.

Figure 3

Two critical phosphorylation sites of Akt has different downstream targets in certain disease conditions. For example Phosphorylation of Akt at T308 significantly increases phosphorylation of PRAS40, TBC1D4 and TSC2 where Phosphorylation of S473 has less effect on these substrates. In similar manner, phosphorylation of S473 significantly increases phosphorylation of BAD. However GSK3 can be phosphorylated by any of the critical phosphorylations on Akt1.

Figure 4

The downstream signals of Akt. Akt stimulates cell growth and proliferation through mTORC1. Akt phosphorylates BAD, epherin receptor, MEKK3, eNOS and MDM2, and up-regulates the activities of these proteins. Direct phosphorylation of caspase-9, YAP, MLK3, GSK3 and FoxO by Akt results in inhibitions of their enzymatic activities. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism.