title: APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis.
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.
authors.affiliation: School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Hong
authors.affiliation: School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Young Doo
authors.initials: YD
authors.lastname: Kim
authors.affiliation: School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Bitna
authors.initials: B
authors.lastname: Lim
authors.affiliation: Graduate School of East-West Medical Science, Kyung Hee University, Gyeoggi-Do 446-701, Korea.
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Won Do
authors.initials: WD
authors.lastname: Heo
authors.affiliation: Department of Surgery, Chonbuk National University Medical School, Jeonju 561-180, Korea.
authors.forename: Doo-Hyun
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Department of Surgery, Chonbuk National University Medical School, Jeonju 561-180, Korea.
authors.forename: Chan-Young
authors.initials: CY
authors.lastname: Kim
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors.forename: Han-Kwang
authors.initials: HK
authors.lastname: Yang
authors.affiliation: Department of Chemistry, College of Natural Sciences, Soongsil University, Seoul 156-743, Korea.
authors.forename: Jin Kuk
authors.initials: JK
authors.lastname: Yang
authors.affiliation: School of Biological Science, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D008875:Middle Aged; D041681:NIH 3T3 Cells; D055503:Protein Multimerization; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D051017:Apoptosis Regulatory Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C573917:APIP protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: APIP; ERBB2; ERBB3; HRG-β1; gastric cancer