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Zhang, Jing

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Jing

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Zhang, Jing

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    CRKL Is an Important Regulator of PI3K Signaling in PTEN-Deficient Tumors
    (2013-09-25) Zhang, Jing; Roberts, Thomas M.; Fisher, David; Blenis, John
    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), \(p110\alpha\) and \(p110\beta\), 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 \(p110\alpha\) and \(p110\beta\) have distinct and redundant functions in normal physiological and disease conditions. For instance, activating mutations in \(p110\alpha\) have been frequently found in human tumors, while mutations in \(p110\beta\) have not been reported. \(p110\alpha\) is required for tumor formation induced by oncogenic RTKs, RAS, or polyoma middle T antigen (MT), whereas \(p110\beta\) 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 \(p110\alpha\) and \(p110\beta\). First, we performed tandem affinity purification and mass spectrometry to look for \(p110\alpha\)- and \(p110\beta\)-interacting proteins. We found that CRKL preferentially binds to \(p110\beta\) at least under overexpression conditions. We further demonstrated that CRKL is an important regulator of PI3K activity in \(p110\beta\)-dependent PTEN-deficient tumor cells. Depletion of CRKL attenuates PI3K signaling and cell growth in PTEN-deficient prostate and breast cancer cell lines, but does not impair AKT activation in HER2 amplified and PIK3CA mutant cancer cells. Moreover, downregulation of CRKL does not inhibit AKT activation stimulated by insulin, suggesting that CRKL might regulate \(p110\beta\) activity in PTEN-null tumors independent of RTK stimulation. In the second part of this thesis, we used knockout fibroblasts and pharmacological inhibitors to dissect functional redundancy of \(p110\alpha\) and \(p110\beta\) in PDGF signaling. Our results suggest that both isoforms function downstream of PDGFR (abundant receptors): \(p110\alpha\) is the major isoform to mediate weak signals while both play a role when the signal is strong. When one isoform is ablated, the other isoform can play a compensatory role in the signal transduction. Such functional redundancy of class IA PI3K isoforms may have implications for the choice of the selectivity of PI3K inhibitors in cancer.