Transglutaminase 3: The Involvement in Epithelial Differentiation and Cancer

Abstract

Transglutaminases (TGMs) contribute to the formation of rigid, insoluble macromolecular complexes, which are essential for the epidermis and hair follicles to perform protective and barrier functions against the environment. During differentiation, epidermal keratinocytes undergo structural alterations being transformed into cornified cells, which constitute a highly tough outermost layer of the epidermis, the stratum corneum. Similar processes occur during the hardening of the hair follicle and the hair shaft, which is provided by the enzymatic cross-linking of the structural proteins and keratin intermediate filaments. TGM3, also known as epidermal TGM, is one of the pivotal enzymes responsible for the formation of protein polymers in the epidermis and the hair follicle. Numerous studies have shown that TGM3 is extensively involved in epidermal and hair follicle physiology and pathology. However, the roles of TGM3, its substrates, and its importance for the integument system are not fully understood. Here, we summarize the main advances that have recently been achieved in TGM3 analyses in skin and hair follicle biology and also in understanding the functional role of TGM3 in human tumor pathology as well as the reliability of its prognostic clinical usage as a cancer diagnosis biomarker. This review also focuses on human and murine hair follicle abnormalities connected with TGM3 mutations.

Identification of Chicken Transglutaminase 1 and In Situ Localization of Transglutaminase Activity in Avian Skin and Esophagus

“…The latter bond is formed under the control of transglutaminases (TGMs) [14]. In the human epidermis, TGM1, TGM3 and TGM5 are implicated in cornified envelope formation [15,16]. TGM1 is anchored to the cell membrane, whereas TGM3 and TGM5 are cytosolic enzymes [17].…”

Ichthyosis: case report in a Colombian man with genetic alterations in ABCA12 and HRNR genes

“…This gene is associated with Uncombable hair syndrome. Other TGM genes are related to ichthyosis, though the TGM3 gene has not been associated with this disease [31]. A variant in the COL7A1 classified as uncertain significance, is believed to alter splicing, but the exact effect is unclear.…”

Deimination, Intermediate Filaments and Associated Proteins

“…In addition to its effect on the sensitivity to proteases, deimination also plays a role in sensitivity to transglutaminases, another family of post-translational modifying enzymes, carrying calcium dependent crosslinking catalytic activities [ 36 , 113 ]. During epidermal differentiation, transglutaminases cross-link proteins, including keratins and IFAP, to the cornified envelopes of corneocytes, and play an important role in the morphogenesis of the hair follicle [ 24 , 25 ].…”

“…Such a mechanism of regulating proteolysis via the deimination of the peptidase inhibitors or peptidase substrates involved therefore seems particularly interesting and should be better deciphered in the future in physiological and pathological contexts. In addition to its effect on the sensitivity to proteases, deimination also plays a role in sensitivity to transglutaminases, another family of post-translational modifying enzymes, carrying calcium dependent crosslinking catalytic activities [36,113]. During epidermal differentiation, transglutaminases cross-link proteins, including keratins and IFAP, to the cornified envelopes of corneocytes, and play an important role in the morphogenesis of the hair follicle [24,25].…”

“…Some IFAP have also been shown to be modified by deimination ( Table 2 and Figure 1 c,d). This modification regulates their sensitivity to proteolysis [ 8 , 30 , 31 , 32 , 33 ] and their ability to be cross-linked by transglutaminases [ 34 , 35 , 36 ], which in turn modulates their structural organization following the loss of positive charges [ 13 ]. The first proteins demonstrated to be deiminated (or citrullinated) by PADs, identified by two-dimensional gel electrophoresis and immunodetection using a specific anti-modified citrulline (AMC) antiserum [ 17 ], were abundant proteins.…”