title: Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers.
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.
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Chaitali
authors.initials: C
authors.lastname: Parikh
authors.forename: Vasantharajan
authors.initials: V
authors.lastname: Janakiraman
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Wu
authors.forename: Catherine K
authors.initials: CK
authors.lastname: Foo
authors.forename: Noelyn M
authors.initials: NM
authors.lastname: Kljavin
authors.forename: Subhra
authors.initials: S
authors.lastname: Chaudhuri
authors.forename: Eric
authors.initials: E
authors.lastname: Stawiski
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Maria N
authors.initials: MN
authors.lastname: Lorenzo
authors.forename: Wenlin
authors.initials: W
authors.lastname: Yuan
authors.forename: Joseph
authors.initials: J
authors.lastname: Guillory
authors.forename: Marlena
authors.initials: M
authors.lastname: Jackson
authors.forename: Jesus
authors.initials: J
authors.lastname: Rondon
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Franke
authors.forename: Krista K
authors.initials: KK
authors.lastname: Bowman
authors.forename: Meredith
authors.initials: M
authors.lastname: Sagolla
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brandhuber
authors.forename: Kui
authors.initials: K
authors.lastname: Lin
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt