Role of the class I(A) phosphoinositide 3-kinase regulatory subunit p85 in metabolism, development and cancer.

摘要

Class IA phosphoinositide 3-kinases (PI3Ks) are heterodimeric lipid kinases consisting of a p85 regulatory subunit and a p110 catalytic subunit. The p85 regulatory subunit stabilizes the p110 catalytic subunit and mediates its receptor recruitment and activation. Upon activation by growth factor receptors, class IA PI3Ks generate the lipid second messenger PIP3 at the plasma membrane. Class IA PI3K signaling critically regulates key cellular processes such as cell metabolism, growth, proliferation and survival. Dysregulation of class IA PI3K signaling is associated with several human diseases such as type-2 diabetes and cancer. My dissertation studies focused on two aspects of class I A PI3K biology: the molecular mechanism by which monomeric p85 negatively regulates class IA PI3K activation, and the in vivo role of class IA PI3K signaling in the context of growth and metabolism.; My studies demonstrated that, in response to IGF-1 signaling, monomeric p85 forms a cytosolic sequestration complex with IRS-1, an adaptor protein that mediates the activation of PI3K downstream of the insulin and the IGF-1 receptors. This sequestration complex prevents IRS-1 from activating p85-p110 heterodimers at the membrane. In addition to cell metabolism, PI3K-mediated cell growth and proliferation is also subjected to negative regulation by monomeric p85, as p85alpha+/- PTEN+/- mice show increased incidence of intestinal polyps and enhanced cell proliferation in the intestinal epithelium compared to PTEN+/- mice. To better understand the roles of class IA PI3Ks in vivo, I generated mice with tissue-specific deletion of p85 proteins. I demonstrated that mice lacking all p85 isoforms in the heart and the muscle show severely impaired PI3K signaling in these tissues, resulting in a reduction in cell and organ size. Furthermore, the loss of muscle PI3K signaling in mice leads to muscle insulin resistance, hyperlipidemia and increased adiposity. Taken together, my dissertation studies demonstrate that class IA PI3K signaling is exquisitely controlled by its p85 regulatory subunit, and class IA PI3K is an important regulator of growth and metabolism in vivo.