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.
Xie
Daxing
D
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Gore
Crystal
C
Zhou
Jian
J
Pong
Rey-Chen
RC
Zhang
Haifeng
H
Yu
Luyang
L
Vessella
Robert L
RL
Min
Wang
W
Hsieh
Jer-Tsong
JT
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D004789:Enzyme Activation; D006706:Homeostasis; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
C462952:DAB2IP protein, human; D020703:ras GTPase-Activating Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048848:MAP Kinase Kinase Kinase 5