FANCI is a negative regulator of Akt activation.
Akt is a critical mediator of the oncogenic PI3K pathway, and its activation is regulated by kinases and phosphatases acting in opposition. We report here the existence of a novel protein complex that is composed minimally of Akt, PHLPP1, PHLPP2, FANCI, FANCD2, USP1 and UAF1. Our studies show that depletion of FANCI, but not FANCD2 or USP1, results in increased phosphorylation and activation of Akt. This activation is due to a reduction in the interaction between PHLPP1 and Akt in the absence of FANCI. In response to DNA damage or growth factor treatment, the interactions between Akt, PHLPP1 and FANCI are reduced consistent with the known phosphorylation of Akt in response to these stimuli. Furthermore, depletion of FANCI results in reduced apoptosis after DNA damage in accord with its role as a negative regular of Akt. Our findings describe an unexpected function for FANCI in the regulation of Akt and define a previously unrecognized intersection between the PI3K-Akt and FA pathways.
a Department of Genetics , University of Texas MD Anderson Cancer Center , Houston , TX , USA.
Xiaoshan
X
Zhang
a Department of Genetics , University of Texas MD Anderson Cancer Center , Houston , TX , USA.
Xiaoyan
X
Lu
a Department of Genetics , University of Texas MD Anderson Cancer Center , Houston , TX , USA.
Shamima
S
Akhter
b Department of Pathology , University of Texas Southwestern Medical Center , Dallas , TX , USA.
Maria-Magdalena
MM
Georgescu
a Department of Genetics , University of Texas MD Anderson Cancer Center , Houston , TX , USA.
Randy J
RJ
Legerski
D017209:Apoptosis; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005199:Fanconi Anemia / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
D052236:Fanconi Anemia Complementation Group D2 Protein; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases
Akt; DNA damage; FANCI; PHLPP; apoptosis; phosphorylation; regulation