title: Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF-like domain independent manner.
abstract: Amphiregulin (AREG), an EGF family protein, is synthesized as a type I transmembrane precursor (proAREG) and expressed on the cell surface with an extracellular EGF-like domain and an intracellular short cytoplasmic tail. The ectodomain shedding yields a soluble EGF receptor ligand (soluble AREG) which binds to EGF receptor (EGFR) and concomitantly induces migration of unshed proAREG from the plasma membrane to the nuclear envelope (NE). AREG is known to play a potential role in breast cancer and has been intensively investigated as an EGF receptor ligand, while the function of the NE-localized proAREG remains unknown. In this study we used a truncated mutant that mimics NE-localized proAREG without shedding stimuli to discriminate between the functions of NE-localized and plasma membrane-localized proAREG and demonstrate that NE-localized proAREG activates breast cancer cell migration, but suppresses cell growth. Moreover, the present study shows that induction of cell migration by NE-localized proAREG does not require the extracellular growth factor domain or EGF receptor function. Collectively these data demonstrate a novel function mediated by the intracellular domain of proAREG and suggest a significant role for NE-localized proAREG in driving human breast cancer progression.
authors.affiliation: Osaka University Graduate School of Medicine and Health Science, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hisae
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yu
authors.initials: Y
authors.lastname: Nishioka
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsuura
authors.forename: Miki
authors.initials: M
authors.lastname: Hieda
mesh_terms: D066258:Amphiregulin; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000819:agonists; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors