Year: 2014
Type: article
Abstract: // Xiangpeng Dai 1,* , Brian J. North 1,* and Hiroyuki Inuzuka 1 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 SCF Fbw7 . 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.
Source: Oncotarget
Institutions: Beth Israel Deaconess Medical Center, Harvard University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Funder: National Institute on Aging
OpenAlex ID: W2140262462