Abstract
Retinoic acid (RA) is a potent activator of tissue transglutaminase (TGase) expression, and it was recently shown that phosphoinositide 3-kinase (PI3K) activity was required for RA to increase TGase protein levels. To better understand how RA-mediated TGase expression is regulated, we considered whether co-stimulation of NIH3T3 cells with RA and epidermal growth factor (EGF), a known activator of PI3K, would facilitate the induction or increase the levels of TGase expression. Instead of enhancing these parameters, EGF inhibited RA-induced TGase expression. Activation of the Ras-ERK pathway by EGF was sufficient to elicit this effect, since continuous Ras signaling mimicked the actions of EGF and inhibited RA-induced TGase expression, whereas blocking ERK activity in these same cells restored the ability of RA to up-regulate TGase expression. However, TGase activity is not antagonistic to EGF signaling. The mitogenic and anti-apoptotic effects of EGF were not compromised by TGase overexpression, and in fact, exogenous TGase expression promoted basal cell growth and resistance to serum deprivation-induced apoptosis. Moreover, analysis of TGase expression and GTP binding activity in a number of cell lines revealed high basal TGase GTP binding activity in tumor cell lines U87 and MDAMB231, indicating that constitutively active TGase may be a characteristic of certain cancer cells. These findings demonstrate that TGase may serve as a survival factor and RA-induced TGase expression requires the activation of PI3K but is antagonized by the Ras-ERK pathway.
Highlights
Tissue transglutaminase (TGase)1 is a member of a family of enzymes that catalyzes a calcium-dependent transamidation reaction that results in the covalent linkage of donor glutamine residues of one protein to acceptor primary amino groups of another protein or polyamine [1, 2]
Retinoic acid (RA) is a potent activator of tissue transglutaminase (TGase) expression, and it was recently shown that phosphoinositide 3-kinase (PI3K) activity was required for RA to increase TGase protein levels
Given that the regulation of TGase expression is linked to PI3K activation and that growth factors frequently activate PI3K, we considered whether cotreatment of NIH3T3 cells with growth factors and RA would potentiate the induction of TGase expression, as well as the level of transamidation or GTP binding activity, compared with RA treatment alone
Summary
Tissue transglutaminase (TGase) is a member of a family of enzymes that catalyzes a calcium-dependent transamidation reaction that results in the covalent linkage of donor glutamine residues of one protein to acceptor primary amino groups of another protein or polyamine [1, 2]. The ability of TGase to transduce signals adds another dimension to its functionality and may help explain how the same protein can be linked to several, sometimes opposing, cellular responses This point is exemplified by the recent finding that a transamidation-defective form of TGase protected cells from heat shock-induced apoptosis [8], indicating that the GTP binding/GTPase activity of TGase likely mediated the survival advantage. The signaling potentials of STAT3, PI3K, and ERK have been shown to increase following RA treatment (20 –22), suggesting that some RA-mediated effects may require the combined activation of certain signaling proteins and the transcriptional capability of the RARs. For some time our laboratory has been interested in understanding the regulation and function of TGase in cells.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
