Identification Of Mutations In Distinct Regions Of P85 Alpha In Urothelial Cancer

Bladder cancers commonly show genetic aberrations in the phosphatidylinositol 3-kinase signaling pathway. Here we have screened for mutations in PIK3R1, which encodes p85 alpha, one of the regulatory subunits of PI3K. Two hundred and sixty-four bladder tumours and 41 bladder tumour cell lines were screened and 18 mutations were detected. Thirteen mutations were in C-terminal domains and are predicted to interfere with the interaction between p85 alpha and p110 alpha. Five mutations were in the BH domain of PIK3R1. This region has been implicated in p110 alpha-independent roles of p85 alpha, such as binding to and altering the activities of PTEN, Rab4 and Rab5. Expression of these mutant BH-p85 alpha forms in mouse embryonic fibroblasts with p85 alpha knockout indicated that all forms, except the truncation mutants, could bind and stabilize p110 alpha but did not increase AKT phosphorylation, suggesting that BH mutations function independently of p110 alpha. In a panel of 44 bladder tumour cell lines, 80% had reduced PIK3R1 mRNA expression relative to normal urothelial cells. This, along with mutation of PIK3R1, may alter BH domain functioning. Our findings suggest that mutant forms of p85 alpha may play an oncogenic role in bladder cancer, not only via loss of ability to regulate p110 alpha but also via altered function of the BH domain.