p37δ is a new isoform of PI3K p110δ that increases cell proliferation and is overexpressed in tumors

The phosphatidylinositol 3-kinases (PI3Ks) regulate cell growth, proliferation and survival, and are frequently affected in human cancer. PI3K is composed of a catalytic subunit, p110, and a regulatory subunit, p85. The PI3K catalytic subunit p110 delta is encoded by PIK3CD and contains p85- and RAS-binding domains, and a kinase domain. Here we present an alternatively spliced PIK3CD transcript encoding a previously unknown protein, p37 delta, and demonstrate that this protein is expressed in human ovarian and colorectal tumors. p37 delta retains the p85-binding domain and a fraction of the RAS-binding domain, lacks the catalytic domain, and has a unique carboxyl-terminal region. In contrast to p110 delta, which stabilizes p85, p37 delta promoted p85 sequestering. Despite the truncated RAS-binding domain, p37 delta bound to RAS and we found a strong positive correlation between the protein levels of p37 delta and RAS. Overexpressing p37 delta, but not p110 delta, increased the proliferation and invasive properties of HEK-293 cells and mouse embryonic fibroblasts. Cells overexpressing p37 delta showed a quicker phosphorylation response of AKT and ERK1/2 following serum stimulation. Ubiquitous expression of human p37 delta in the fruit fly increased body size, DNA content and phosphorylated ERK1/2 levels. Thus, p37 delta appears to be a new tumor-specific isoform of p110 delta with growth-promoting properties. Oncogene (2012) 31, 3277-3286; doi: 10.1038/onc.2011.492; published online 24 October 2011