Extracellular TG2: emerging functions and regulation

Abstract

Tissue transglutaminase (TG2) is a ubiquitously expressed member of the transglutaminase family of Ca(2+)-dependent crosslinking enzymes. Unlike other family members, TG2 is a multifunctional protein, which has several other well documented enzymatic and non-enzymatic functions. A significant body of evidence accumulated over the last decade reveals multiple and complex activities of this protein on the cell surface and in the extracellular matrix (ECM), including its role in the regulation of cell-ECM interactions and outside-in signaling by several types of transmembrane receptors. Moreover, recent findings indicate a dynamic regulation of the levels and functions of extracellular TG2 by several complementary mechanisms. This review summarizes and assesses recent research into the emerging functions and regulation of extracellular TG2.

Fig. 1

Several types of TG2-containing adhesive / signaling complexes present on the cell surface. Solid black lines indicate TG2-mediated activation of cytoplasmic targets by transmembrane signaling receptors. Dotted black line marks binding of activated PKCα to the integrin cytoplasmic tails, which causes their redistribution on the cell surface. Red dashed line outlines the activation of syndecan-2 by intracellular PKCα, and green dashed line - syndecan-2-mediated activation of ROCK, which induces stress fiber and focal adhesion formation. Blue dashed line marks nuclear translocation of β-catenin which leads to its complex formation with Tcf/Lef and activation of gene transcription. Curved black line indicates the principal pathway of surface TG2 internalization.

Fig. 2

The unconventional pathway of cytoplasmic TG2 secretion involves phospholipid-dependent delivery into recycling endosomes. Solid lines mark the major endosomal recycling pathway which operates via the perinuclear recycling endosomal compartment. Dashed line indicates the PI(3)P-dependent recruitment of cytoplasmic TG2 to the membranes of the perinuclear recycling compartment.

Fig. 3

The constitutive LRP1-dependent internalization and lysosomal degradation of cell surface TG2. Solid lines mark the major endosomal recycling and lysosomal degradative pathways.