Identification of Transglutaminase 3 Splicing Isoforms

Loredana Zocchi, Alessandro Terrinoni, Eleonora Candi, Bijan Ahvazi, Giacinto Bagetta, M. Tiziana Corasaniti, Anna M. Lena and Gerry Melino


Journal of Investigative Dermatology (2007) 127, 1791–1794


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Transglutaminases (TGs) are a family of nine Ca2þ-dependent enzymes (types 1–7, band 4.2, factor XIII) that catalyze cross-linking reaction resulting in the formation of an Ne-(g-glutamyl lysine) isopeptide bound between their substrates (Griffin et al., 2002; Lorand and Graham, 2003; Esposito and Caputo, 2005). TG-modified proteins are more resistant to proteolytic degradation and play a role in different biological processes such as bone ossification and cell–matrix interactions (TG2), blood coagulation (factor XIII), semen clotting (TG4), and epithelial differentiation (TG1, TG3, and TG5) (Kim et al., 1995b; Candi et al., 2002; Lorand and Graham, 2003; Candi et al., 2005; Eckert et al., 2005). Four members (types 1–3, and 5) expressed in stratified squamous epithelia such as the epidermis, and during the differentiation process, are responsible for the formation of the cornified cell envelope (Kalinin et al., 2002; Candi et al., 2005). TG1 enzyme is expressed all over the epidermis (from the lower to the upper layers); the enzyme becomes highly active on proteolitically processing, which occurs in the upper layers of the epidermis. TG1 cross-links structural proteins, including involucrin, loricrin, and small proline-rich proteins, mutations abolishing its activity cause lamellar ichthyosis (MIM 242300) in human, whereas TG1 / mice die soon after birth owing to incomplete barrier function of the skin (Matsuki et al., 1998; Kuramoto et al., 2002). TG5 (Grenard et al., 2001) is expressed in the upper layers of human epidermis (Candi et al., 2002) and in human hair follicle (Thibaut et al., 2005), mutations abolishing its activity are associated to acral peeling skin syndrome (MIM 609796) in human (Cassidy et al., 2005). TG3 is expressed in the epidermis in the late differentiation stages (Kim et al., 1995a; Lee et al., 1996) and in the inner root sheath and in the medullary layers of hair follicles, as well as in the stomach, brain, and testis (Hitomi et al., 2001). The native TG3 protein has a molecular mass of 77 kDa, both in human and mice, it is proteolitically activated in a 47-kDa component, containing the catalytic core and a 30-kDa fragment (Ahvazi et al., 2003, 2004a). Recently, it has been shown that, at least in vitro, cathepsin L is able to cleave and activate TG3 (Cheng et al., 2006). TG3, similar to TG1 and TG5, crosslinks small proline-rich proteins, loricrin, and involucrin during the formation of the cell envelope. In vivo and in vitro data show that these enzymes (TG1, TG3, and TG5) use different glutamine and lysine residues (Hitomi et al., 2001) in the same protein substrate, indicating that they act synergistically to generate a functional cell envelope. To date, no mutations or disease are associated with TG3. Finally, TG3 also seems involved in signal transduction and, like two other TGs (TG2 and TG5), is able to bind and hydrolyze guanosine triphosphate (Liu et al., 2002; Ahvazi et al., 2003; Ahvazi et al., 2004a b; Candi et al. (2004)).


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