AKT2 Function and Oncogenic Activity

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DESCRIPTION: (provided by applicant) Like other AKT/protein kinase B family members, AKT2 is activated by growth factors through phosphatidylinositol 3-kinase (PI3K) and thereby mediates signals involved in diverse cellular processes such as apoptosis inhibition, cell proliferation, and insulin signaling. The AKT2 gene is unique among members of the AKT family, in that it is preferentially expressed in tissues targeted by insulin and is amplified/overexpressed in some human pancreatic and ovarian carcinomas. In addition, activation of the AKT2 kinase appears to be common occurrence in these tumor types. Moreover, AKT2 activation up-regulates IGF-I receptor expression and promotes invasiveness of pancreatic cancer cells in response to exogenous IGF-I. The broad, long-term objective of this project is to elucidate the normal cellular function of AKT2 and determine the significance of AKT2 perturbations in pancreatic cancer. The proposed experiments test the hypothesis that AKT2 plays an important role in normal development, and that aberrant expression/activation of AKT2 contributes to the development of progression of some pancreatic carcinomas. The specific aims are fourfold: 1) Delineate the phenotype of Akt2 knockout mice to elucidate the function of Akt2 in normal embryonic development and in adult tissues. In addition to the phenotypic/histologic characterization, metabolic studies of Akt2 (-/-) mice and derived cells will be carried out to determine the role of Akt2 in insulin metabolism. The effect of pro-apoptotic stimuli will be examined to determine if loss of Akt2 decreases resistance to programmed cell death. 2) Determine the mechanistic role of AKT2 expression/activity in human pancreatic cancer and in a mouse cancer model. AKT2 expression and activity will be evaluated in human pancreatic tumors and early lesions. To determine the mechanism(s) of AKT2 activation in pancreatic cancers, PTEN protein expression and P13K activity will be investigated. To elucidate the mechanistic role of Akt2 in oncogenesis, Akt2 (-/-) mice will be crossed with PTEN (+/-) mice to determine if loss of the Akt2 isoform alone is capable of diminishing oncogenesis associated with PTEN loss. 3) Determine if IGF-1 plays a significant role in pancreatic cancer cell invasiveness in connection with AKT2 activation and with AKT2-mediated IGF-IR overexpression. Furthermore, collagenolytic assays will be employed to define the mechanisms involved in this process. 4) Characterize the interaction between AKT2 and a novel adaptor APPL, cloned in this laboratory. The role of APPL in apoptosis inhibition and oncogenesis will be delineated. Overall, the proposed investigations will yield important insights regarding AKT2 function and oncogenic mechanisms.