Oncotarget

Research Papers:

Negative regulation of DAB2IP by Akt and SCFFbw7 pathways

Xiangpeng Dai, Brian J. North _ & Hiroyuki Inuzuka

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Oncotarget. 2014; 5:3307-3315. https://doi.org/10.18632/oncotarget.1939

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Abstract

Xiangpeng Dai1,*, Brian J. North1,* and Hiroyuki Inuzuka1

1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

* These authors contributed equally to this work.

Correspondence: Brian North, email: bnorth @bidmc.harvard.edu

Correspondence: Hiroyuki Inuzuka, email: hinuzuka@bidmc.harvard.edu

Keywords: DAB2IP, Akt, Fbw7, degradation, cancer, phosphorylation, ubiquitination.

Received: April 16, 2014 Accepted: April 30, 2014 Published: May 1, 2014

Abstract

Deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), is a tumor suppressor that serves as a scaffold protein involved in coordinately regulating cell proliferation, survival and apoptotic pathways. DAB2IP is epigenetically down-regulated in a variety of tumors through the action of the histone methyltransferase EZH2. Although DAB2IP is transcriptionally down-regulated in a variety of tumors, it remains unclear if other mechanisms contribute to functional inactivation of DAB2IP. Here we demonstrate that DAB2IP can be functionally down-regulated by two independent mechanisms. First, we identified that Akt1 can phosphorylate DAB2IP on S847, which regulates the interaction between DAB2IP and its effector molecules H-Ras and TRAF2. Second, we demonstrated that DAB2IP can be degraded in part through the ubiquitin-proteasome pathway by SCFFbw7. DAB2IP harbors two Fbw7 phosho-degron motifs, which can be regulated by the kinase CK1δ. Our data indicate that in addition to epigenetic down-regulation, two additional pathways can functionally inactivate DAB2IP. Given that DAB2IP has previously been identified to possess direct causal role in tumorigenesis and metastasis, our data indicate that a variety of pathways may pass through DAB2IP to govern cancer development, and therefore highlight DAB2IP agonists as potential therapeutic approaches for future anti-cancer drug development.


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