The p85 Regulatory Subunit of PI3K Mediates cAMP-PKA and Insulin Biological Effects on MCF-7 Cell Growth and Motility

Abstract EN

Recent studies have shown that hyperinsulinemia may increase the cancer risk.

Moreover, many tumors demonstrate an increased activation of IR signaling pathways.

Phosphatidylinositol 3-kinase (PI3K) is necessary for insulin action.

In epithelial cells, which do not express GLUT4 and gluconeogenic enzymes, insulin-mediated PI3K activation regulates cell survival, growth, and motility.

Although the involvement of the regulatory subunit of PI3K ( p 85 α PI 3 K ) in insulin signal transduction has been extensively studied, the function of its N-terminus remains elusive.

It has been identified as a serine (S83) in the p 85 α PI 3 K that is phosphorylated by protein kinase A (PKA).

To determine the molecular mechanism linking PKA to insulin-mediated PI3K activation, we used p 85 α PI 3 K mutated forms to prevent phosphorylation (p85A) or to mimic the phosphorylated residue (p85D).

We demonstrated that phosphorylation of p 85 α PI 3 K S83 modulates the formation of the p 85 α PI 3 K / IRS - 1 complex and its subcellular localization influencing the kinetics of the insulin signaling both on MAPK-ERK and AKT pathways.

Furthermore, the p 85 α PI 3 K S83 phosphorylation plays a central role in the control of insulin-mediated cell proliferation, cell migration, and adhesion.

This study highlights the p 85 α PI 3 K S83 role as a key regulator of cell proliferation and motility induced by insulin in MCF-7 cells breast cancer model.