TIG3: a regulator of type I transglutaminase activity in epidermis.

Keratinocytes undergo a process of terminal cell differentiation that results in the construction of a multilayered epithelium designed to produce a structure that functions to protect the body from dehydration, abrasion and infection. These protective properties are due to the production of a crosslinked layer of protein called the cornified envelope. Type I transglutaminase (TG1), an enzyme that catalyzes the formation of epsilon-(gamma-glutamyl)lysine bonds, is the key protein responsible for generation of the crosslinks.

Localization of the TIG3 transglutaminase interaction domain and demonstration that the amino-terminal region is required for TIG3 function as a keratinocyte differentiation regulator.

Tazarotene-induced gene 3 (TIG3) regulates keratinocyte terminal differentiation by activating type I transglutaminase (TG1). TIG3 consists of an amino-terminal (N-terminal) segment, that encodes several conserved motifs, and a carboxy-terminal (C-terminal) membrane-anchoring domain. By producing a series of truncation mutants that remove segments of the N-terminal region, and monitoring the ability of each mutant to co-precipitate TG1, function as a TG1 substrate, or functionally localize with TG1 in cells, we show that the TIG3 domain that interacts with TG1 is located within a TIG3 segment spanning amino acids 112-164.

A novel transglutaminase activator forms a complex with type 1 transglutaminase.

Type I transglutaminase is a plasma membrane-anchored intracellular protein-protein crosslinking enzyme that is responsible for assembly of the keratinocyte cornified envelope during terminal keratinocyte differentiation. We recently described a novel protein, TIG3, that when expressed in keratinocytes causes increased transglutaminase activity and keratinocyte cell death. However, the mechanism of activation of transglutaminase by TIG3 is not known.

Transglutaminase function in epidermis.

Surface epithelial cells, such as the epidermal keratinocyte, undergo a process of terminal cell differentiation that results in the construction of a multilayered epithelium. This epithelium functions to protect the organism from the environment. Transglutaminases, enzymes that catalyze the formation of isopeptide protein-protein cross-links, are key enzymes involved in the construction of this structure.

Human epidermal keratinocytes undergo (-)-epigallocatechin-3-gallate-dependent differentiation but not apoptosis.

Epigallocatechin-3-gallate (EGCG) is an important chemopreventive agent derived from green tea. We recently reported that EGCG treatment enhances keratinocyte differentiation as evidenced by increased human involucrin promoter activity [Balasubramanian,S., Efimova,T.

A novel tumor suppressor protein promotes keratinocyte terminal differentiation via activation of type I transglutaminase.

Tazarotene-induced protein 3 (TIG3) is a recently discovered regulatory protein that is expressed in the suprabasal epidermis. In the present study, we show that TIG3 regulates keratinocyte viability and proliferation. TIG3-dependent reduction in keratinocyte viability is accompanied by a substantial increase in the number of sub-G1 cells, nuclear shrinkage, and increased formation of cornified envelope-like structures.