Oncotarget

Research Papers:

Smurf1 regulation of DAB2IP controls cell proliferation and migration

Xiaoning Li, Xiangpeng Dai, Lixin Wan, Hiroyuki Inuzuka, Liankun Sun _ and Brian J. North

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Oncotarget. 2016; 7:26057-26069. https://doi.org/10.18632/oncotarget.8424

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Abstract

Xiaoning Li1,2,*, Xiangpeng Dai2,*, Lixin Wan2, Hiroyuki Inuzuka2, Liankun Sun1, Brian J. North2

1Department of Pathophysiology, Basic Medical College, Jilin University, Changchun 130021, China

2Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

*These authors contributed equally to this work

Correspondence to:

Liankun Sun, email: [email protected]

Brian J. North, email: [email protected]

Keywords: DAB2IP, Smurf1, Akt, degradation, cancer

Received: November 19, 2015     Accepted: March 07, 2016     Published: March 27, 2016

ABSTRACT

Tumor cell proliferation, survival and migration are regulated by the deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), a tumor suppressor that serves as a scaffold protein for H-Ras and TRAF2. Importantly, the oncogenic histone methyl-transferase EZH2 epigenetically down-regulates DAB2IP in a variety of tumors. Recently, we demonstrated that DAB2IP is negatively regulated by Akt-dependent phosphorylation and SCFFbw7-mediated degradation. Here, we further identify the oncoprotein Smurf1, an E3-ubiquitin ligase, as a novel negative regulator of DAB2IP. Smurf1-mediated cellular proliferation and migration are largely dependent on the presence of DAB2IP, suggesting that DAB2IP is a key effector molecule of Smurf1 oncogenic function. Additionally, we identify that similar to DAB2IP, Smurf1 is also a target of phosphorylation by both Akt1 and Akt2 kinases, which enhances Smurf1 abundance, leading to a reduction in DAB2IP. Given the role of DAB2IP in tumorigenesis and metastasis, our data identify Smurf1 as an upstream oncogenic factor that negatively regulates DAB2IP to govern aberrant cell growth and migration.


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