Functional analysis of carboxy-terminal peptide signaling of pro-amphiregulin and pro-epiregulin

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Amphiregulin (AREG) and epiregulin (EREG), members of the EGF family, are synthesized as type I transmembrane protein precursors (proAREG and proEREG) and expressed on the cell surface. Shedding of proAREG and proEREG yield transmembrane-cytoplasmic fragments (AREGF-CTF and EREG-CTF), as well as soluble forms AREG and EREG. Here we demonstrated that the ectodomain shedding stimuli triggered endocytosis of both their CTFs and un-shed forms. They translocated from the plasma membrane to the nuclear membrane via retrograde membrane trafficking. Nuclear envelope localization of proAREG involves truncation of the C-terminus, which subsequently activates the ER-retrieval signal. The truncated form of proAREG interacts with A-type lamin and is retained at the inner nuclear membrane. Heterochromatin formation is then induced and global transcription is transiently suppressed. This study gives new insight into epigenetic chromatin organization in mammalian cells : a plasma-membrane-anchored growth factor is targeted to the inner nuclear membrane where it participates in dynamic chromatin organization and control of transcription.