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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.

Pubmed ID: 19903888


  • Xie D
  • Gore C
  • Zhou J
  • Pong RC
  • Zhang H
  • Yu L
  • Vessella RL
  • Min W
  • Hsieh JT


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 24, 2009

Associated Grants


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