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Transglutaminase 3: the Involvement in Epithelial Differentiation and Cancer

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Transglutaminase 3: the Involvement in Epithelial Differentiation and Cancer cells Review Transglutaminase 3: The Involvement in Epithelial Differentiation and Cancer Elina S. Chermnykh * , Elena V. Alpeeva and Ekaterina A. Vorotelyak Koltzov Institute of Developmental Biology Russian Academy of Sciences, 119334 Moscow, Russia; [email protected] (E.V.A.); [email protected] (E.A.V.) * Correspondence: [email protected] Received: 1 June 2020; Accepted: 26 August 2020; Published: 30 August 2020 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. Keywords: transglutaminase; hair follicle; epidermis; cornification; carcinoma 1. Introduction Many physiologically important protein cross-linking reactions in mammals are orchestrated by transglutaminases (TGMs). These enzymes catalyze the formation of the protein network by introducing isopeptide bonds between lysine and glutamine residues of the target proteins [1,2]. TGMs are also engaged in the deamidation reaction of glutamine residues, the covalent conjugation of polyamines and the lipid esterification [3,4]. The primary purpose of TGM-mediated posttranslational protein modification is the formation of stabilized and insoluble protein polymer structures, such as a cornified cell envelope (CCE), a hair fiber, bones, or a fibrin clot [2]. Some TGMs may function as atypical GTPases and ATPases, protein disulfide isomerases, protein kinases, and also have non-enzymatic functions associated with cell signaling and cell–matrix interactions [5,6]. Depending on the distribution in organs and tissues, TGMs are classified into separate groups known as TGM types. In humans, nine types of TGMs, TGM1-7, Factor XIII and Band 4.2, have been documented and characterized. These enzymes fulfill a variety of physiological functions and are related to different pathological processes [2,6]. All mammalian TGMs have structural homology, although they can display the differences in their N- and C-terminal domains [7,8]. All TGMs except Band 4.2 were found to be expressed in the integument system at the mRNA level [9,10]; however, the contribution to the skin development of three of them (TGM4, TGM7, Factor XIII) remains to be investigated. TGM4 is thought to be exclusively involved in prostate gland morphogenesis and is present in the seminal plasma [11]. The function of TGM7, Cells 2020, 9, 1996; doi:10.3390/cells9091996 www.mdpi.com/journal/cells Cells 2020, 9, 1996 2 of 19 showingCells 20 widespread20, 9, x FOR PEER distribution REVIEW in different tissues with high expression pattern restricted2 toof 20 testes and lungs, remains unclear [12]. Factor XIII was unequivocally confirmed to play a role in the fibrin clot stabilizationpresent in [13 the], butseminal recent plasma studies [11]. suggest The function it to be involvedof TGM7, inshowing corneal widespread epithelium distribution maintenance in and cornealdifferent wound tissues healing with process high expression [14]. As for pattern the Band restricted 4.2, it to is testes related and to thelungs, regulation remains ofunclear the shape [12]. and mechanicalFactor XIII properties was unequivocally of erythrocytes confirmed [15]. to The play remaining a role in the five fibrin TGMs clot stabilization are determined [13], but to berecent of great importancestudies forsuggest epidermal it to be and involved hair follicle in corneal morphogenesis epithelium (Tablemaintenance1) playing and mainly corneal a wound structural healing role and process [14]. As for the Band 4.2, it is related to the regulation of the shape and mechanical properties are distributed in all epidermal layers (Figure1). Mutations in some of them result in dermatological of erythrocytes [15]. The remaining five TGMs are determined to be of great importance for epidermal pathologies. TGM1 makes a predominant contribution to CCE formation. The inborn error in TGM1 and hair follicle morphogenesis (Table 1) playing mainly a structural role and are distributed in all geneepidermal in mice results layers in(Figure an absence 1). Mutations of CCE in and some impaired of them skinresult barrier in dermatological function [16 pathologies.]. TGM2, inTGM1 contrast, is thoughtmakes a to predominant play a minor contribution role in keratinocyte to CCE formation. CCE assembly,The inborn sinceerror in mice TGM1 lacking gene in TGM2 mice results are viable, phenotypicallyin an absence normal, of CCE and and do impaired not show skin skin barrier barrier function defects [16]. [17 TGM2,]. According in contrast, tosome is thought authors, to play TGM2 a is constitutivelyminor role expressed in keratinocyte in all epidermalCCE assembly, layers since [18]; mice however, lacking other TGM2 authors are wereviable, able phenotypically to detect TGM2 onlynormal, in basal and keratinocytes do not show under skin barrier specific defects conditions, [17]. According such as to wound some authors, healing TGM2 and repair is constitutively (Figure1) [ 19]. Althoughexpressed TGM2 in all does epidermal not seem layers to play[18]; however, the central other role authors in the were epidermis, able to itdetect has beenTGM2 recently only in basal revealed as a mediatorkeratinocytes of the under epidermal specific conditions, inflammatory such response as wound to healing UV irradiation and repair [(Figure18]. TGM2 1) [19]. is alsoAlthough localized in dermalTGM2 fibroblastsdoes not seem and to contributes play the central to extracellular role in the epidermis, matrix formation it has been via recently binding revealed fibronectin as a and mediator of the epidermal inflammatory response to UV irradiation [18]. TGM2 is also localized in collagens together [20]. TGM2 is found in numerous tissues and is implicated in multiple processes, dermal fibroblasts and contributes to extracellular matrix formation via binding fibronectin and including wound healing, proliferation, apoptosis, cell adhesion, and migration [21,22]. TGM5 plays an collagens together [20]. TGM2 is found in numerous tissues and is implicated in multiple processes, importantincludin roleg wound in keratinocyte healing, proliferation, differentiation apoptosis, and the cell cornification adhesion, and of themigration epidermis, [21,22]. since TGM5 its epidermalplays expressionan important is altered role in in diseases keratinocyte related differentiation to abnormal keratinization,and the cornification such as of psoriasis the epidermis, and ichthyosis since its [23]. TGM6epidermal is associated expression with neuronalis altered in differentiation diseases related [24 to], abnormal but its high keratinization, expression such was alsoas psoriasis detected and in the skinichthyosis [25]. TGM6 [23]. was TGM6 mapped is associated in close with proximity neuronal to TGM3differentiation on chromosome [24], but its 20 high in humans expression and was shares morealso than detected a 50% in sequence the skin similarity[25]. TGM6 to was it. mapped The donor in close substrates proximity of TGM6 to TGM3 and on Ca chromosome++-binding 20 sites in are similarhumans to those and ofshares TGM3 more [25 ].than This a 50% signature sequence allows similarity us to to suggest it. The TGM6donor substrates involvement of TGM6 in epidermal and differentiation.Ca++-binding TGM1,sites are TGM3, similar TGM5, to those and of TGM6TGM3 [25]. are widelyThis signature expressed allows in epidermalus to suggest keratinocytes TGM6 beinginvolvement mainly responsible in epidermal for differentiation. the cross-linking TGM1, of proteinsTGM3, TGM5, to form and CCE TGM6 in are the widely skin epidermis expressed andin to epidermal keratinocytes being mainly responsible for the cross-linking of proteins to form CCE in the strengthen hair fiber [26–28]. skin epidermis and to strengthen hair fiber [26–28]. FigureFigure 1. Distribution1. Distribution of of transglutaminases transglutaminases (TGMs) (TGMs) in in the the epidermis. epidermis. The mainThe main focus focus of this of reviewthis revi isew TGM3, is TGM3, also also referred referred to as to epidermal as epidermal TGM. TGM. This This enzyme enzyme was was initially discoveredinitially indiscovered the hair fiberin the and hair hair fiber follicle and hair [29 follicle,30], and [29,30], was subsequentlyand was subsequently found infound
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