PADI4 and tumourigenesis

Peptidylarginine deiminase (PAD) can catalyse peptidyl arginine to citrulline in the presence of Ca2+ ions, a reaction known as citrullination, which leads to the post-translational modification of proteins. Genes encoding PAD family members, including PADI1, PADI2, PADI3, PADI4, and PADI6, cluster at human chromosome position 1p36.13. The high sequence identity of the C-terminal domains of all PADs suggests that their structures are similar [1]. The expression of all of these isoforms has been detected in numerous tissues. PADI1 is found in the skin epidermis [2], PADI2 is present in various tissues including brain and muscle [3,4], PADI3 is localised in hair follicles [5], PADI4 is mainly expressed in granulocytes and monocytes [6], and PADI6 is specially expressed in embryonic stem cells and oocytes [7,8]. Studies have reported that PADs are involved in cell differentiation, apoptosis, nerve growth, embryonic development, and gene regulation [9]. Biochemical and immunohistochemical assays have suggested the involvement of PADI1 in the terminal differentiation of the epidermis [10], PADI2 in the myelination and citrullination of central nerve axons [11,12], and PADI3 in the keratinisation of hair follicles [3,13]. Arginine residues frequently function as ligand recognition sites in proteins. Some enzymes that interact with negatively charged substrates or cofactors have an arginine residue as an anion recognition site [14]. Therefore, it seems possible that PADs and citrullination participate in the regulation of these enzymes. In addition, PAD citrullination was suggested to modify the action of trypsin-like enzymes [15] and trypsin inhibitors [14], to interfere with intermediate filament assembly [16], and to play a role in rapid cellular turnover in tissues with secretory activity [17]. However, the physiological significance of each of the PADs has not been understood in detail.PADI4 was initially cloned from the HL-60 cell line (human promyelocytic leukaemia