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

Oncogene. 2012 Jul 5;31(27):3277-86. doi: 10.1038/onc.2011.492. Epub 2011 Oct 24.

Abstract

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 p110δ 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, p37δ, and demonstrate that this protein is expressed in human ovarian and colorectal tumors. p37δ 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 p110δ, which stabilizes p85, p37δ promoted p85 sequestering. Despite the truncated RAS-binding domain, p37δ bound to RAS and we found a strong positive correlation between the protein levels of p37δ and RAS. Overexpressing p37δ, but not p110δ, increased the proliferation and invasive properties of HEK-293 cells and mouse embryonic fibroblasts. Cells overexpressing p37δ showed a quicker phosphorylation response of AKT and ERK1/2 following serum stimulation. Ubiquitous expression of human p37δ in the fruit fly increased body size, DNA content and phosphorylated ERK1/2 levels. Thus, p37δ appears to be a new tumor-specific isoform of p110δ with growth-promoting properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Body Size / genetics
  • Cell Proliferation
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Down-Regulation
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neoplasm Invasiveness
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • ras Proteins / metabolism

Substances

  • Isoenzymes
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ia Phosphatidylinositol 3-Kinase
  • PIK3CD protein, human
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • ras Proteins