Signaling specificity in the Akt pathway in biology and disease

Adv Biol Regul. 2014 May;55:28-38. doi: 10.1016/j.jbior.2014.04.001. Epub 2014 Apr 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Enzyme Activation
  • Humans
  • Lamin Type A / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Multiprotein Complexes / metabolism
  • Nuclear Proteins / metabolism
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Protein Isoforms / metabolism*
  • Protein Phosphatase 2 / metabolism
  • Protein Structure, Tertiary / physiology
  • Proto-Oncogene Proteins c-akt / chemistry
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / physiology
  • Substrate Specificity
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Lamin Type A
  • Multiprotein Complexes
  • Nuclear Proteins
  • Protein Isoforms
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2