APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis

// Se-Hoon Hong 1, * , Won Jae Lee 1, * , Young Doo Kim 1 , Hyunjoo Kim 1 , Young-Jun Jeon 1 , Bitna Lim 1 , Dong-Hyung Cho 2 , Won Do Heo 3 , Doo-Hyun Yang 4 , Chan-Young Kim 4 , Han-Kwang Yang 5 , Jin Kuk Yang 6 , Yong-Keun Jung 1 1 School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea 2 Graduate School of East-West Medical Science, Kyung Hee University, Gyeoggi-Do 446-701, Korea 3 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea 4 Department of Surgery, Chonbuk National University Medical School, Jeonju 561-180, Korea 5 Department of Surgery, Seoul National University College of Medicine, Seoul 110-744, Korea 6 Department of Chemistry, College of Natural Sciences, Soongsil University, Seoul 156-743, Korea * These authors have contributed equally to this work Correspondence to: Yong-Keun Jung, e-mail: ykjung@snu.ac.kr Keywords: ERBB3, ERBB2, HRG-β1, gastric cancer, APIP Received: July 17, 2015 Accepted: February 20, 2016 Published: March 01, 2016 ABSTRACT 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.