Transglutaminase 2 in disease (NIH/R01)

The unique roles of the GTP-binding protein/crosslinking enzyme transglutaminase-2 in disease

Abstract
Tissue transglutaminase (TGase-2) is a GTP-binding protein/protein crosslinking enzyme implicated in various pathological conditions including coeliac disease, neurodegenerative disorders, and aggressive cancers. The mechanistic basis by which TGase-2 contributes to many of these disorders is poorly understood. Recently, we obtained exciting new clues regarding the roles of TGase-2 in human cancers from discoveries identifying it as a novel EGF receptor (EGFR)-signaling partner, that ensures high levels of EGFR expression by protecting EGFRs against the actions of c-Cbl, as well as serves as a scaffold to mediate PI-3K activation. TGase-2 expression is inversely correlated with the survival of brain cancer patients, and is uniquely expressed together with the EGFRvIII, an oncogenic variant of the EGFR, in an extremely aggressive subset of glioma initiator (stem) cells (GSCs), called mesenchymal (MES) GSCs.  Importantly, TGase-2 and EGFRvIII are also among the cargo of microvesicles (MVs) shed by MES GSCs, offering a potential mechanism by which MES GSCs transfer these important signaling proteins to surrounding cells to re-program their microenvironment. In this proposal, we will build on these discoveries to establish the mechanisms by which TGase-2 contributes to disease states. We will focus on its role in glioblastoma (GBM) through the combined efforts of two laboratories with complimentary expertise in EGFR-signaling (Cerione) and translational studies of GSCs (Nakano), as follows: 1) Test the hypothesis that TGase-2 plays novel roles in the actions of the oncogenic EGFRvIII and other receptors implicated in GBM. Based on our recent findings, we will determine whether TGase-2 adversely affects patient survival by protecting the EGFRvIII, and other receptors linked to GBM, against c-Cbl-catalyzed degradation and/or by enhancing their signaling to PI-3K/Akt/mTORC1. 2) Test the hypothesis that the EGFRvIII and TGase-2 play an essential part in the intercellular signaling mediated by MVs from MES GSCs. We will determine whether these MVs transfer the EGFRvIII and TGase-2 to less aggressive GSCs or to differentiated cancer cells, to re-program them for tumor formation. 3) Test the idea that targeting TGase-2 through different strategies blocks the actions of MES GSCs in mouse models for GBM. The expectation is these studies will be broadly relevant toward understanding the biological roles of TGase-2 in disease, as well as identify novel therapeutic targets for EGFR/EGFRvIII-driven cancers such as GBM.