# The unique roles of the GTP-binding/protein crosslinking enzyme transglutaminase-2 and signaling partners in aggressive cancers

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $433,417

## Abstract

Abstract - Our laboratories have focused on understanding how the EGF receptor (EGFR) and its signaling
partner, the GTP-binding/protein crosslinking enzyme tranglutaminase-2 (TGase-2), contribute to
aggressive cancers, and discovered that TGase-2 enhances EGFR signaling by blocking its degradation by
c-Cbl. The goals of CA201402 were then to examine whether TGase-2 provides a similar protective effect
for the EGFR oncogenic variant, EGFRvIII, in glioma stem cells (GSCs), and if these proteins are important
for the actions of their extracellular vesicles (EVs). Our efforts have resulted in a number of new discoveries,
which form the basis of this renewal application. These include the finding that TGase-2 function is coupled
to its ability to adopt two distinct conformational states, a GTP-bound closed state that protects EGFRs from
Cbl-catalyzed degradation, and a protein crosslinking-competent open-state that binds to large EVs, called
microvesicles (MVs), and is necessary for their ability to influence the tumor microenvironment and stimulate
angiogenesis. However, when TGase-2 is induced to adopt an open state within cancer cells, it causes cell
death. Although we found that EGFRvIII does not require TGase-2 to protect it from Cbl-catalyzed
ubiquitylation, we discovered EGFRvIII expression is coupled to glutamine metabolism which is elevated in
aggressive cancer cells. Moreover, we found aggressive cancer cells generate large numbers of small EVs
(exosomes) that contain the immune checkpoint ligand, PD-L1, and the cell survival protein Survivin, due to
their elevated glutamine metabolism and their down-regulation of Sirtuin 1 (SIRT1), an NAD+-dependent
deacetylase. We will now set out to understand the consequences of these discoveries for the growth and
survival of GSCs, through the efforts of two laboratories with complimentary expertise in cancer cell signaling
(Cerione) and translational studies of GSCs (Nakano), as follows: 1) Determine how to exploit the open-
state conformation of TGase-2 to inhibit cancer cell viability. We will establish how open-state TGase-2
causes cancer cells to undergo cell death and develop methods to stabilize that state as a potential
therapeutic strategy. 2) Understand how EGFRvIII expression in aggressive GSCs is coupled to glutamine
metabolism. We will determine why inhibiting glutamine metabolism markedly affects the cellular levels of
EGFRvIII expression, and whether EGFRvIII expression and signaling stimulate the production of MVs
containing this oncogenic variant and TGase-2. 3) Understand the connection between the expression of
EGFRvIII and TGase-2 in aggressive GSCs and the shedding of large numbers of exosomes with unique
protein cargo. We will establish whether down-regulation of SIRT1 in GSCs, and signaling pathways
involving EGFRvIII and/or TGase-2, are responsible for their ability to produce large numbers of exosomes
enriched in PD-L1 and Survivin. These studies will provide new insights into ...

## Key facts

- **NIH application ID:** 10839816
- **Project number:** 5R01CA201402-10
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** RICHARD A. CERIONE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $433,417
- **Award type:** 5
- **Project period:** 2015-12-04 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839816

## Citation

> US National Institutes of Health, RePORTER application 10839816, The unique roles of the GTP-binding/protein crosslinking enzyme transglutaminase-2 and signaling partners in aggressive cancers (5R01CA201402-10). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10839816. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*