APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis
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Se-Hoon Hong1,*, Won Jae Lee1,*, Young Doo Kim1, Hyunjoo Kim1, Young-Jun Jeon1, Bitna Lim1, Dong-Hyung Cho2, Won Do Heo3, Doo-Hyun Yang4, Chan-Young Kim4, Han-Kwang Yang5, Jin Kuk Yang6, Yong-Keun Jung1
1School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea
2Graduate School of East-West Medical Science, Kyung Hee University, Gyeoggi-Do 446-701, Korea
3Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea
4Department of Surgery, Chonbuk National University Medical School, Jeonju 561-180, Korea
5Department of Surgery, Seoul National University College of Medicine, Seoul 110-744, Korea
6Department of Chemistry, College of Natural Sciences, Soongsil University, Seoul 156-743, Korea
*These authors have contributed equally to this work
Yong-Keun Jung, e-mail: [email protected]
Keywords: ERBB3, ERBB2, HRG-β1, gastric cancer, APIP
Received: July 17, 2015 Accepted: February 20, 2016 Published: March 01, 2016
Despite the fact that the epidermal growth factor (EGF) family member ERBB3 (HER3) is deregulated in many cancers, the list of ERBB3-interacting partners remains limited. Here, we report that the Apaf-1-interacting protein (APIP) stimulates heregulin-β1 (HRG-β1)/ERBB3-driven cell proliferation and tumorigenesis. APIP levels are frequently increased in human gastric cancers and gastric cancer-derived cells. Cell proliferation and tumor formation are repressed by APIP downregulation and stimulated by its overexpression. APIP's role in the ERBB3 pathway is not associated with its functions within the methionine salvage pathway. In response to HRG-β1, APIP binds to the ERBB3 receptor, leading to an enhanced binding of ERBB3 and ERBB2 that results in sustained activations of ERK1/2 and AKT protein kinases. Furthermore, HRG-β1/ERBB3-dependent signaling is gained in APIP transgenic mouse embryonic fibroblasts (MEFs), but not lost in Apip−/− MEFs. Our findings offer compelling evidence that APIP plays an essential role in ERBB3 signaling as a positive regulator for tumorigenesis, warranting future development of therapeutic strategies for ERBB3-driven gastric cancer.
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