DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis.

In metastatic prostate cancer (PCa) cells, imbalance between cell survival and death signals such as constitutive activation of phosphatidylinositol 3-kinase (PI3K)-Akt and inactivation of apoptosis-stimulated kinase (ASK1)-JNK pathways is often detected. Here, we show that DAB2IP protein, often down-regulated in PCa, is a potent growth inhibitor by inducing G(0)/G(1) cell ...
cycle arrest and is proapoptotic in response to stress. Gain of function study showed that DAB2IP can suppress the PI3K-Akt pathway and enhance ASK1 activation leading to cell apoptosis, whereas loss of DAB2IP expression resulted in PI3K-Akt activation and ASK1-JNK inactivation leading to accelerated PCa growth in vivo. Moreover, glandular epithelia from DAB2IP(-/-) animal exhibited hyperplasia and apoptotic defect. Structural functional analyses of DAB2IP protein indicate that both proline-rich (PR) and PERIOD-like (PER) domains, in addition to the critical role of C2 domain in ASK1 activity, are important for modulating PI3K-Akt activity. Thus, DAB2IP is a scaffold protein capable of bridging both survival and death signal molecules, which implies its role in maintaining cell homeostasis.
Mesh Terms:
Animals, Apoptosis, Cell Cycle, Cell Line, Cell Survival, Enzyme Activation, Homeostasis, Humans, MAP Kinase Kinase Kinase 5, Male, Mice, Mice, Knockout, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms, Proto-Oncogene Proteins c-akt, RNA Interference, Signal Transduction, ras GTPase-Activating Proteins
Proc. Natl. Acad. Sci. U.S.A.
Date: Nov. 24, 2009
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