Title: CRKL is an important regulator of PI3K signaling in PTEN-deficient tumors
Description: In response to signals mediated by receptor tyrosine kinases (RTKs), G protein-coupled receptors or oncogenes, the two ubiquitously expressed isoforms of class IA phosphatidylinositol-3-kinases (PI3Ks), p110α and p110β, generate lipid second messengers at plasma membrane, which elicit multiple signal transduction cascades that regulate a broad range of cellular processes such as cell survival, proliferation, adhesion, motility, and transformation. Despite their similarity in sequence, expression pattern and regulatory subunits, growing evidence suggests that p110α and p110β have distinct and redundant functions in normal physiological and disease conditions. For instance, activating mutations in p110α have been frequently found in human tumors, while mutations in p110β have not been reported. p110α is required for tumor formation induced by oncogenic RTKs, RAS, or polyoma middle T antigen (MT), whereas p110β seems to be essential for PTEN-deficient tumors. The objective of my dissertation has been to investigate the mechanisms underlying isoform selectivity and functional redundancy of p110α and p110β.