Abstract
The protein kinase v-akt murine
thymoma viral oncogene homolog (AKT), a key regulator of cell survival and
proliferation, is frequently hyperactivated in human cancers. Intramolecular
pleckstrin homology (PH) domain-kinase domain (KD) interactions are important
in maintaining AKT in an inactive state. AKT activation proceeds after a
conformational change that dislodges the PH from the KD. To understand these
autoinhibitory interactions, we generated mutations at the PH-KD interface and
found that most of them lead to constitutive activation of AKT. Such mutations
are likely another mechanism by which activation may occur in human cancers and
other diseases. In support of this likelihood, we found somatic mutations in
AKT1 at the PH-KD interface that have not been previously described in human
cancers. Furthermore, we show that the AKT1 somatic mutants are constitutively
active, leading to oncogenic signaling. Additionally, our studies show that the
AKT1 mutants are not effectively inhibited by allosteric AKT inhibitors,
consistent with the requirement for an intact PH-KD interface for allosteric
inhibition. These results have important implications for therapeutic
intervention in patients with AKT mutations at the PH-KD interface.
Source: Disruption
of PH-kinase domain interactions leads to oncogenic activation of AKT in human
cancers. Parikh C, Janakiraman V, Wu WI, Foo CK, Kljavin NM, Chaudhuri S,
Stawiski E, Lee B, Lin J, Li H, Lorenzo MN, Yuan W, Guillory J, Jackson M,
Rondon J, Franke Y, Bowman KK, Sagolla M, Stinson J, Wu TD, Wu J, Stokoe D,
Stern HM, Brandhuber BJ, Lin K, Skelton NJ, Seshagiri S (sekar@gene.com). Proc
Natl Acad Sci U S A. 2012 Nov 7.
Free paper available at:
http://www.pnas.org/content/early/2012/11/07/1204384109.long
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