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

Daxing Xie, Crystal Gore, Jian Zhou, Rey Chen Pong, Haifeng Zhang, Luyang Yu, Robert L. Vessella, Wang Min, Jer Tsong Hsieh

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

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/G1 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.

Original languageEnglish (US)
Pages (from-to)19878-19883
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number47
DOIs
StatePublished - Nov 24 2009

Keywords

  • Cell apoptosis
  • Prostate cancer
  • Signal transduction

ASJC Scopus subject areas

  • General

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