Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF-like domain independent manner
- Osaka University Graduate School of Medicine and Health Science, 1-7 Yamadaoka, Suita, Osaka 565-0871 (Japan)
- Proteo Medicine Research Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295 (Japan)
Highlights: Black-Right-Pointing-Pointer Nuclear envelope-localized proAREG activates cancer cell migration via its cytoplasmic domain. Black-Right-Pointing-Pointer The induction of cell migration does not require the EGF-like domain or EGR function. Black-Right-Pointing-Pointer Nuclear envelope-localized proAREG suppresses breast cancer cell growth without EGFR function. Black-Right-Pointing-Pointer This study revealed a novel function mediated by the intracellular domain of proAREG. -- 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.
- OSTI ID:
- 22207814
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 420, Issue 4; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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