Transglutaminase-2 (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 by identifying it as a unique EGF receptor (EGFR)-signaling partner. Specifically, we found TGase-2 enhances EGFR expression by protecting EGFRs against the actions of c-Cbl, as well as functions as a novel scaffold to mediate PI-3K activation. TGase-2 expression is inversely correlated with brain cancer survival, and it is specifically expressed together with an oncogenic variant of the EGFR, the EGFRvIII, in a highly aggressive subset of glioma initiator (stem) cells (GSCs), called mesenchymal (MES) GSCs. Moreover, TGase-2 and EGFRvIII are 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 reprogram 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, as well as 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 TGase-2 and the EGFRvIII play an essential part in the intercellular signaling mediated by MVs from MES GSCs. We will determine whether this extremely aggressive sub-set of GSCs use MVs to `communicate' with less aggressive GSCs or with 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.

Public Health Relevance

Transglutaminase-2 has been implicated in a number of disease states including neurodegenerative disorders and aggressive forms of human cancer. Recently, we determined how TGase-2 serves as a unique signaling partner for the EGF receptors, which now provides important clues regarding how TGase-2 contributes to various diseased states, and especially to the development of high-grade brain cancer. The hope is that this information will also highlight new therapeutic strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Yassin, Rihab R
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Cornell University
Other Basic Sciences
Schools of Veterinary Medicine
United States
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Katt, William P; Blobel, Nicolas J; Komarova, Svetlana et al. (2018) A small molecule regulator of tissue transglutaminase conformation inhibits the malignant phenotype of cancer cells. Oncotarget 9:34379-34397
Cerione, Richard A (2018) The experiences of a biochemist in the evolving world of G protein-dependent signaling. Cell Signal 41:2-8
Sadahiro, Hirokazu; Kang, Kyung-Don; Gibson, Justin T et al. (2018) Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma. Cancer Res 78:3002-3013
Huang, Qingqiu; Stalnecker, Clint; Zhang, Chengliang et al. (2018) Characterization of the interactions of potent allosteric inhibitors with glutaminase C, a key enzyme in cancer cell glutamine metabolism. J Biol Chem 293:3535-3545
Antonyak, Marc A; Cerione, Richard A (2018) The distinct traits of extracellular vesicles generated by transformed cells. Small GTPases 9:427-432
Lukey, Michael J; Katt, William P; Cerione, Richard A (2018) Targeting Therapy Resistance: When Glutamine Catabolism Becomes Essential. Cancer Cell 33:795-797
Katt, William P; Antonyak, Marc A; Cerione, Richard A (2018) The diamond anniversary of tissue transglutaminase: a protein of many talents. Drug Discov Today 23:575-591
Pavlyukov, Marat S; Yu, Hai; Bastola, Soniya et al. (2018) Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors. Cancer Cell 34:119-135.e10
Lukey, Michael J; Katt, William P; Cerione, Richard A (2017) Targeting amino acid metabolism for cancer therapy. Drug Discov Today 22:796-804
Yoo, Sungsoo M; Latifkar, Arash; Cerione, Richard A et al. (2017) Cool-associated Tyrosine-phosphorylated Protein 1 Is Required for the Anchorage-independent Growth of Cervical Carcinoma Cells by Binding Paxillin and Promoting AKT Activation. J Biol Chem 292:3947-3957

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