Open AccessAPIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis
Author(s) -
Seung Wook Hong,
Won Jae Lee,
Young Doo Kim,
HyunJoo Kim,
Young-Jun Jeon,
Bitna Lim,
DongHyung Cho,
Won Do Heo,
Doo-Hyun Yang,
Chan Young Kim,
HanKwang Yang,
Jin Kuk Yang,
YongKeun Jung
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.7802
Subject(s) - erbb3 , carcinogenesis , medicine , cancer , cancer research , oncology , gerontology , epidermal growth factor receptor
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.