A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Abstract

Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.

Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias

“…However, the SSCP from the tumours did not reveal any aberrantly migrating band compared with the wild-type bands from the normal tissues (data not shown). We repeated the experiments twice, including tissue microdissection, PCR, SSCP and DNA sequencing analysis to ensure the specificity of the results and found that the data were consistent.Because the previous study showed modest incidences of AKT1 E17K mutation (up to 8.2%) in a wide range of the cancers (Carpten et al, 2007), we expected to detect comparable AKT1 E17K mutations in our cancer specimens. However, we detected the AKT1 E17K mutation in the breast cancers (4.3%), but not in other cancers.…”

“…The AKT1 mutation was a missense mutation that substituted an amino acid (E17K) in the PH domain of AKT1. The AKT1 E17K mutation was found in 5 out of 61 (8.2%) breast cancers, 3 out of 51 (5.9%) colorectal cancers and 1 out of 50 (2.0%) ovarian cancers (Carpten et al, 2007). The E17K mutation was mutually exclusive with respect to PIK3CA mutation and loss of PTEN expression (Carpten et al, 2007).…”

“…Inactivating mutation of PTEN and activating mutation of PIK3CA have been detected in many human cancers and have been known as major activating mechanisms of AKTsignalling pathway in cancers (Testa and Bellacosa, 2001;Samuels et al, 2004). By contrast, activating mutation of AKT genes has not been widely reported in human cancers.Recently, a research group discovered a recurrent somatic mutation of AKT1 gene in human breast, colorectal and ovarian cancers (Carpten et al, 2007). The AKT1 mutation was a missense mutation that substituted an amino acid (E17K) in the PH domain of AKT1.…”

“…The E17K mutation was mutually exclusive with respect to PIK3CA mutation and loss of PTEN expression (Carpten et al, 2007). Functionally, the AKT1 E17K mutation stimulates AKT signalling, induces cellular transformation and produces leukaemia in mice, strongly suggesting that this mutation may play a crucial role in cancer development (Carpten et al, 2007).To further characterise the AKT1 E17K mutation in human cancers, the following questions were investigated in this study: (a) whether human cancer tissues from various histologic origins have the AKT1 E17K mutation; (b) whether there is any ethnic difference of the AKT1 E17K mutation incidence in breast and colorectal cancers; and (c) whether any corresponding mutation of AKT1 E17K occurs in AKT2 or AKT3 genes. …”

Opposing roles of the oncogene Akt isoforms in tumour progression: is there a dark side to Akt pathway inhibition?

“…Properly regulated activation of Akt depends on the integrity of the pleckstrin homology (PH) domain, which mediates its membrane translocation and subsequent phosphorylation at two regulatory sites, Thr308 in the kinase activation loop, and Ser473 in the C-terminal domain of the Akt family, only AKT2 mRNA is frequently overexpressed in human cancers [17]. Activation of Akt can also result from a dominant mutation that was identified in human tumours [3] and a point mutation of AKT2 has been reported in familial diabetes [9]. Ectopic expression of constitutively active Akt and even wild-type Akt2 results in oncogenic transformation in vitro and in vivo [4].…”