Signaling specificity in the Akt pathway in biology and disease

Abstract

Akt/PKB is a key master regulator of a wide range of physiological functions including metabolism, proliferation, survival, growth, angiogenesis and migration and invasion. The Akt protein kinase family comprises three highly related isoforms encoded by different genes. The initial observation that the Akt isoforms share upstream activators as well as several downstream effectors, together with the high sequence homology suggested that their functions were mostly redundant. By contrast, an increasing body of evidence has recently uncovered the concept of Akt isoform signaling specificity, supported by distinct phenotypes displayed by animal strains genetically modified for each of the three genes, as well as by the identification of isoform-specific substrates and association with discrete subcellular locations. Given that Akt is regarded as a promising therapeutic target in a number of pathologies, it is essential to dissect the relative contributions of each isoform, as well as the degree of compensation in pathophysiological function. Here we summarize our view of how Akt selectivity is achieved in the context of subcellular localization, isoform-specific substrate phosphorylation and context-dependent functions in normal and pathophysiological settings.

Keywords: Akt; Cancer; Nucleus; PI 3-Kinase; Protein kinase; Signaling.

Figure 1

Structure of Akt isoforms. All Akt isoforms possess a catalytic domain (KD), flanked by an amino-terminal PH domain and by a regulatory domain at the carboxyl-terminus. Phosphorylation sites in the activation loop of the catalytic domain and in the regulatory domain turn loop and hydrophobic motif are highlighted in red. The chromosome location of the genes coding for the Akt isozymes and the percentage of sequence homology are also indicated.

Figure 2

Regulation of Akt phosphorylation. PI 3-K activated downstream of RTKs phosphorylates PIP2 generating PIP3. PDK1 and Akt are transiently docked to the membrane by their PIP3-binding module, the PH domain, thereby exposing their catalytic domain. By this mechanism, PDK1 and Akt relocate in close proximity to one another and PDK1 phosphorylates Akt at Thr308. Phosphorylation at Ser473 is carried out by mTORC2, leading to full activation of Akt which then redistributes to discrete subcellular locations where it phosphorylates target proteins containing the RxRxxS/T motif. Dephosphorylation of PIP3 by PTEN, and direct dephosphorylation of Akt by PP2A at Thr308 and PHLPP at Ser473 all contribute to terminate Akt signaling. Abbreviations: mTORC2, mammalian target of rapamycin complex 2; PDK-1, phosphoinositide-dependent kinase 1; PH, pleckstrin homology; PHLPP, PH domain leucine-rich repeat protein phosphatase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5- trisphosphate; PP2A, protein phosphatase 2A; PTEN, phosphatase and tensin homolog deleted on chromosome ten; RTK, receptor tyrosine kinase.

Figure 3

Components of the two mTOR complexes. mTORC1 is composed of mTOR, mLST8, raptor and PRAS40, and is sensitive to rapamycin. Besides mLST8, the rapamycin-insensitive mTORC2 complex contains mTOR in association with rictor, mSIN1 and PRR5.