Carboxy-ternminal fragment signaling of membrane-anchored growth factors the EGF family

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A key step for signaling through the epidermal growth factor receptor (EGFR) is the release of mature ligands such as heparin-binding EGF-like growth factor (HB-EGF) from their membrane-anchored precursor forms, a process termed "ectodomain shedding". The HB-EGF precursor (proHB-EGF) is cleaved by members of the "a disintegrin and metalloprotease" (ADAM) protease family, yielding the carboxyl terminal fragment of proHB-EGF (HB-EGF-CTF) in parallel with the production of HB-EGF. We have previously characterized HB-EGF-CTF as a novel intracellular signaling molecule acquired posttranslationally which is translocated into the nucleus, binding and inactivating the promyelocytic leukemia zinc finger protein (PLZF). PLZF is a transcriptional repressor that suppresses the transcription of genes such as c-MYC, Cyclin A2, and HoxD11. Activation of growth factor receptors by ligand binding leads to increased expression of c-Myc, a transcriptional regulator for cell proliferation. The activation … More of transcriptional factors through the activated receptors has been thought to be a main role in the c-Myc gene expression. We demonstrate here that EGFR-,FGFR-, and PDGFR-mediated c-Myc induction and cell cycle progression in the primary cultured mouse embryonic fibroblasts (MEFs) are abrogated by knockout of the heparin-binding EGF-like growth factor (Hb-egf) gene, or by a metalloproteinase inhibitor, although the downstream of the receptors is activated. The induction of c-Myc expression by EGF or bFGF recovers in the Hb-egf-knockouted MEFs by overexpression of wildtype proHB-EGF, though no recovery with an uncleavable mutant of proHB-EGF. It is also observed that the uncleavable mutant inhibits the EGF-induced acetylation of histone H3 at the mouse c-Myc first intron region which negatively affects the transcriptional activation. We conclude that the signal transduction initiated by generation of the carboxyl terminal fragment of proHB-EGF (HB-EGF-CTF) in the shedding event can play an essential intermediary role between growth factor receptor activation and c-Myc gene induction. Less