Physiological early response in tissue repair and regeneration -molecular mechanism of shedding : Analyses in wound healing model

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1) TPA-dependent HB-EGF shedding was completely abrogated in ADAM12-/- mouse-derived embryonic fibroblast, but not in ADAM9-/- mouse-derived embryonic fibroblast, suggesting that ADAM12 is a key enzyme in HB-EGF shedding.2) In order to analyze the activation mechanism of ADAM12, we screened proteins to bind the cytoplasmic of ADAM12 using a yeast two-hybrid method, resulting in the identification of two kinds of SH3 domain-containing proteins, PACSIN3 and a novel one designated Eve-1. PACSIN3 consists of 416 amino acids and has three SH3 domains in the C-terminal region. Eve-1 has two spliced isoforms, Eve-1a and Eve-1b which consists 767 and 790 amino acids, respectively. Eve-1a and Eve-1b have four and five SH3 domains in the C-terminal region. Overexpression of PACSIN3 and Eve-1a suppressed additively TPA-HB-EGF shedding.Based on these data, we speculated that HB-EGF shedding would be regulated multiply by ADAM members and SH3 domain containing proteins.