Physiological and Pathological Roles of Class IA Phosphoinositide 3-Kinases p110alpha and p110beta.

Abstract

Class I phosphatidylinositol 3-kinases (PI3Ks) are enzymes that phosphorylate the 3'-OH of the inositol moiety of the membrane lipid phosphatidylinositol 4,5-bisphosphate. These enzymes are divided into subclasses IA and IB. Class IA PI3Ks play essential roles in regulating cell growth, survival and metabolism. They are also strongly implicated in the development of human cancers. There are three class IA PI3K catalytic isoforms, p110alpha, p110beta and p110delta. Currently, it is unclear what are their distinct biological functions. For my thesis research, I used genetically engineered mice to study the roles of p110alpha and p110beta in the regulation of heart contraction, the maintainence of skeletal muscle mass and the development of pancreatic cancer. Ablation of p110alpha or p110beta alone in cardiac myocytes resulted in a relatively mild or minimal phenotype, respectively. However, mice lacking both p110alpha and p110beta died less than 40 days after birth with 100% penetrance. The Ca2+-handling system that is essential for excitation-contraction coupling was severely disrupted in the double PI3K-null myocytes. The second component of my thesis research investigated PI3Ks in the skeletal muscle. Mice lacking p110alpha had smaller skeletal muscle mass than wild type animals, whereas loss of p110beta did not affect muscle mass. By contrast, mice lacking PTEN, a phosphatase that antagonizes PI3K signaling, had increased skeletal muscle mass. Insulin-like growth factor-1 activation of PI3K signaling was blocked in the p110alpha-null, but not p110beta-null, muscles. The final component of my thesis research investigated the role of PI3Ks in oncogenic Kras-induced pancreatic tumors. Kras mutations are found in > 90% of human pancreatic ductal adenocarcinomas (PDA). Oncogenic Kras-induced PDA in a mouse model was completely blocked by genetic deletion of p110alpha but not affected by the loss of p110beta. These studies indicate that PI3K p110alpha and p110beta play distinct roles in regulating different physiological and pathological functions in a tissue-specific manner. These results may have clinical implications for the use of PI3K inhibitors in the treatment of diseases such as cancer.