To understand the pathophysiological role of ACK1 signaling, 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, on right). These PB-ACK1 transgenic mice display ACK1 activation and significant increase in AKT Tyr176-phosphorylation leading to Ser473/Thr308-phosphorylation in prostates (Figure B, top 3 panels). These mice developed prostatic intraepithelial neoplasia or mPINs and adenoarcinomas (Figure E).

ACK1 mediated AKT Tyr176-phosphorylation and activation may be more proximal stage initiating processes in neoplastic progression that serve as an alternative to those of PTEN loss which has been shown in other mouse models of prostate cancer. Thus, ACK1 activation could be an independent tumor initiation event in those cancer patients that exhibit normal PTEN and PI3K, but still exhibit AKT activation.