AKT plays a central role in tumorigenesis

Abstract

AKT is emerging as a central player in tumorigenesis. In this issue of PNAS, Mayo and Donner (1) report on yet another function of AKT, involving regulation of the Mdm2/p53 pathway. The first evidence pointing to a role of AKT in oncogenesis was provided by early studies of transforming viruses. A novel retrovirus, isolated from an AKR mouse T cell lymphoma (2), harbored transduced sequences of cellular origin (3). In 1991, our collaborative studies with Philip Tsichlis and Stephen Staal resulted in the cloning of the viral oncogene v- akt (4). The predicted oncoprotein contained viral Gag sequences fused to a kinase related to protein kinase C. The oncogenic potential of v-akt arises from the creation of a myristylation site at the amino terminus and consequent constitutive kinase activity (5). By different approaches, aimed at identifying novel protein kinases, two other groups independently cloned the identical cellular sequence at about the same time (6, 7). AKT is now known to define a family of closely related, highly conserved cellular homologues (reviewed in ref. 8). In human, these are designated AKT1 , AKT2 , and AKT3 , located at chromosomes 14q32, 19q13, and 1q44, respectively (reviewed in ref. 9). The encoded proteins are serine/threonine kinases belonging to the protein kinase B (PKB) family, and the AKT1, AKT2, and AKT3 proteins are also known as PKBα, PKBβ, and PKBγ, respectively. Each AKT family member contains an amino-terminal pleckstrin homology (PH) domain, a short α-helical linker, and a carboxyl-terminal kinase domain (8). PH domains exist in diverse signaling molecules and permit anchorage of proteins to the cell membrane via phospholipid interactions (10). The degree of functional redundancy between AKT1, AKT2, and AKT3 is currently unclear. Although each kinase responds similarly to various stimuli, their different tissue-specific expression patterns suggest distinct roles, …