TGM3
TGM3 (transglutaminase 3) encodes a calcium-dependent protein cross-linking enzyme that plays a central role in epidermal terminal differentiation and hair follicle morphogenesis through the formation of highly insoluble protein polymers and the cornified cell envelope.[1] During keratinocyte differentiation, TGM3 catalyzes the cross-linking of structural proteins including loricrin, involucrin, and small proline-rich proteins, thereby strengthening epithelial barrier integrity and supporting tissue cornification.[1][2] Mechanistically, TGM3 is activated during the late stages of epithelial differentiation and contributes to the assembly of protein networks that stabilize epidermal and hair shaft architecture.[1][3] In hair follicles, TGM3 participates in the cross-linking of trichohyalin, keratins, and keratin-associated proteins, supporting inner root sheath formation and hair shaft structural organization.[1] Dysregulation of TGM3 has been linked to epithelial malignancies, where altered expression frequently correlates with differentiation status and tumor progression.[1] In cutaneous squamous cell carcinoma, reduced TGM3 expression is associated with poor differentiation, increased recurrence, enhanced epithelial-mesenchymal transition, and activation of the PI3K-AKT signaling pathway.[4] Experimental evidence further indicates that TGM3 suppresses tumor cell proliferation, migration, and invasion while promoting keratinocyte differentiation through regulation of KRT14 stability.[4] Compared with other epidermal transglutaminase isoforms such as TGM1 and TGM5, TGM3 is particularly associated with hair follicle keratinization and trichohyalin cross-linking, highlighting its distinct contribution to epidermal and follicular differentiation programs.[1][2] Although selective TGM3-targeted pharmacological modulators remain limited, manipulation of TGM3 expression and downstream PI3K-AKT signaling has emerged as a useful experimental strategy for investigating epithelial differentiation and squamous carcinoma biology.[4]
References:
- [1]. Chermnykh ES, et al. Transglutaminase 3: The Involvement in Epithelial Differentiation and Cancer. Cells. 2020 Aug 30;9(9):1996. [Content Brief]
- [2]. Smirnov A, et al. Transglutaminase 3 is expressed in basal cell carcinoma of the skin. Eur J Dermatol. 2019 Oct 1;29(5):477-483. doi: 10.1684/ejd.2019.3636. PMID: 31647461. [Content Brief]
- [3]. Lee MJ, et al. Time to HIV rebound after infusion of long-acting broadly neutralising antibodies 3BNC117-LS and 10-1074-LS and analytical treatment interruption (the RIO trial): a double-blind, randomised, placebo-controlled trial. Lancet HIV. 2026 May 27:S2352-3018(26)00059-7. [Content Brief]
- [4]. Zhou K, et al. Transglutaminase 3 regulates cutaneous squamous carcinoma differentiation and inhibits progression via PI3K-AKT signaling pathway-mediated Keratin 14 degradation. Cell Death Dis. 2024 Apr 8;15(4):252. [Content Brief]
