Myristoylated p110? Causes Embryonic Death Due to Developmental and Vascular Defects.

ABSTRACT: The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many important cellular functions. The functional impact of deregulating the PIK3CA gene, encoding the p110? catalytic subunit of PI3K, is validated by frequent gain of function mutations in a range of human cancers. We generated a mouse model with an inducible constitutively active form of PI3K. In this model Cre recombinase activates expression of a myristoylated form of p110? (myr-p110?). The myristoylated version of p110? brings the protein to the cytoplasmic side of the cell membrane, which mimics the normal activation mechanism for the p110? catalytic subunit and activates the PI3K enzyme. Constitutively activated PI3K signaling induced by myr-p110? in all cells of the developing mouse caused lethality during embryonic development. Transgenic Cre;myr-p110? heterozygous embryos displayed morphological malformation and poor vascular development with extremely dilated blood vessels and hemorrhage in the embryo and the extraembryonic yolk sac. Previous studies demonstrated that loss of p110? during embryonic development causes angiogenic disruption and here we show that constitutive activation of p110? by gain of function mutation during development also disrupts vasculogenesis/angiogenesis in what appears to be a similar manner. These finding demonstrate the importance of tight regulation of PI3K signaling during embryonic vasculogenesis/angiogenesis..

SUBMITTER: Sheen MR 

PROVIDER: S-EPMC4966669 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature