To understand the pathophysiological role of Ack1/AKT signaling pathway we generated a transgenic mouse model in which Myc-tagged activated Ack1 was expressed under the control of modified Probasin (PB) promoter, ARR2PB (Figure A). PB-Ack1 transgenic mice display significant increase in AKT Tyr176-phosphorylation leading to Ser473/Thr308-phosphorylation (Figure B, top 3 panels) in the prostates (Figure B, panel 2). These mice developed intraepithelial hyperplasia by 22 weeks (Figure D) and mPINs by 44 weeks (Figure E).
Ack1 mediated AKT Tyr176-phosphorylation and activation may be more proximal stage initiating processes in neoplastic progression that mimic or serve as an alternative to those of PTEN loss which has been prominently emphasized in other mouse models of prostate cancer .
Mahajan K et al. PLoS One. 2010;5(3):e9646
Probasin-Ack1 transgenic mice display pTyr176-AKT and develop mPINs. (A) Transgenic construct (Prob-Ack1) is shown. (B) Prostate lysates from 21 and 25 wk old TG and the WT siblings were IB with respective antibodies. The bottom 2 panels represent tail-PCR of these mice. IL-2 was an internal control for PCR. (C–E) Haematoxylin and eosin (H&E) stained WT and TG mice prostates. Histological appearance of the prostate lateral lobe from a 22 wk old WT mouse (C), and corresponding lobe from age-matched TG mice with intraepithelial hyperplasia (D). The lateral prostate from 49 wk old TG mice exhibiting mPIN (E) is shown.