Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

Kim, Nayeon; Kang, Joo‐Hyon; Lee, Won Kyu; Kim, Seul Gi; Lee, Jae Seon; Lee, Seon-Hyeong; Park, Jong Bae; Kim, Kyung Hee; Gong, Young Dae; Hwang, Kwang Yeon; Kim, Soo Youl

doi:10.1007/s00726-018-2635-2

Cited by 11 publications

(25 citation statements)

References 24 publications

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“…In cancer, TGase 2 knock down causes down regulation of cancer progression because the roles of TGase 2 in cancer converge, promoting cancer progression by way of adhesion, proliferation, and EMT (reviewed in [44,83]). TGase 2 knock down or inhibition by single targeting specifically induces an anti-cancer effect in ccRCC through stabilization of p53, because p53 binds directly to TGase 2 and is thus chaperoned to the autophagosome for degradation [19][20][21]23,67,71]. This is only possible in ccRCC because over 90% of p53 in ccRCC is wild type.…”

Section: Discussionmentioning

confidence: 99%

“…This is only possible in ccRCC because over 90% of p53 in ccRCC is wild type. Thus, collectively these observations represent a breakthrough for the clinical field because they identify TGase 2 as a specific therapeutic target for ccRCC, and the marked potential for binding inhibitors between TGase 2 and p53 such as GK921 [71] and streptonigrin [23] to become the first therapeutics for ccRCC (reviewed in [64]).…”

Section: Discussionmentioning

confidence: 99%

“…(D) TGase 2 expression is also induced by anti-cancer drug treatment along with drug resistance through NF-B activation [42,70]. All of these pathways can be reversed by a single treatment of GK921 [71] or streptonigrin [23], which binds to the N-terminus of TGase 2 where p53 would bind, prior to transfer to the autophagosome in ccRCC [64].…”

Section: Figurementioning

confidence: 99%

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A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Kim

Keillor

2020

IJMS

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In a recent report, no significance of transglutaminase 2 (TGase 2) was noted in the analyses of expression differences between normal and clear cell renal cell carcinoma (ccRCC), although we found that knock down of TGase 2 induced significant p53-mediated cell death in ccRCC. Generally, to find effective therapeutic targets, we need to identify targets that belong specifically to a cancer phenotype that can be differentiated from a normal phenotype. Here, we offer precise reasons why TGase 2 may be the first therapeutic target for ccRCC, according to several lines of evidence. TGase 2 is negatively regulated by von Hippel-Lindau tumor suppressor protein (pVHL) and positively regulated by hypoxia-inducible factor 1-α (HIF-1α) in renal cell carcinoma (RCC). Therefore, most of ccRCC presents high level expression of TGase 2 because over 90% of ccRCC showed VHL inactivity through mutation and methylation. Cell death, angiogenesis and drug resistance were specifically regulated by TGase 2 through p53 depletion in ccRCC because over 90% of ccRCC express wild type p53, which is a cell death inducer as well as a HIF-1α suppressor. Although there have been no detailed studies of the physiological role of TGase 2 in multi-omics analyses of ccRCC, a life-long study of the physiological roles of TGase 2 led to the discovery of the first target as well as the first therapeutic treatment for ccRCC in the clinical field.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Kim

Keillor

2020

IJMS

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“…The most important finding of the present work is that the induction of tumor remission after TGase 2 inhibition is associated with increased stability of p53. Recently, we showed that GK921 binds to the N-terminus of TGase 2 (aa 81–116), which stabilizes p53 by blocking TGase 2 binding [ 30 , 31 ]. Binding of GK921 to the N-terminus of TGase 2 also deactivates TGase 2 through non-covalent self-polymerization of TGase 2, which is induced via a conformational change [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we showed that GK921 binds to the N-terminus of TGase 2 (aa 81–116), which stabilizes p53 by blocking TGase 2 binding [ 30 , 31 ]. Binding of GK921 to the N-terminus of TGase 2 also deactivates TGase 2 through non-covalent self-polymerization of TGase 2, which is induced via a conformational change [ 31 ]. TGase 2 contains an extracellular trafficking sequence at the N-terminus (aa 88–106) of the β-sandwich domain [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition

Lee

Kim

et al. 2018

Cancers

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In general, expression of transglutaminase 2 (TGase 2) is upregulated in renal cell carcinoma (RCC), resulting in p53 instability. Previous studies show that TGase 2 binds to p53 and transports it to the autophagosome. Knockdown or inhibition of TGase 2 in RCC induces p53-mediated apoptosis. Here, we screened a chemical library for TGase 2 inhibitors and identified streptonigrin as a potential therapeutic compound for RCC. Surface plasmon resonance and mass spectroscopy were used to measure streptonigrin binding to TGase 2. Mass spectrometry analysis revealed that streptonigrin binds to the N-terminus of TGase 2 (amino acids 95–116), which is associated with inhibition of TGase 2 activity in vitro and with p53 stabilization in RCC. The anti-cancer effects of streptonigrin on RCC cell lines were demonstrated in cell proliferation and cell death assays. In addition, a single dose of streptonigrin (0.2 mg/kg) showed marked anti-tumor effects in a preclinical RCC model by stabilizing p53. Inhibition of TGase 2 using streptonigrin increased p53 stability, which resulted in p53-mediated apoptosis of RCC. Thus, targeting TGase 2 may be a new therapeutic approach to RCC.

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The transglutaminase 2 cancer cell survival factor maintains mTOR activity to drive an aggressive cancer phenotype

Chen

Adhikary

Newland

et al. 2022

Molecular Carcinogenesis

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Transglutaminase 2 (TG2) is an important cancer stem-like cell survival protein that is highly expressed in epidermal squamous cell carcinoma and drives an aggressive cancer phenotype. In the present study, we show that TG2 knockdown or inactivation results in a reduction in mammalian target of rapamycin (mTOR) level and activity in epidermal cancer stem-like cells which are associated with reduced spheroid formation, invasion, and migration, and reduced cancer stem cell and epithelial-mesenchymal transition (EMT) marker expression. Similar changes were observed in both cultured cells and tumors. mTOR knockdown or treatment with rapamycin phenocopies the reduction in spheroid formation, invasion, and migration, and cancer stem cell and EMT marker expression. Moreover, mTOR appears to be a necessary mediator of TG2 action, as a forced expression of constitutively active mTOR in TG2 knockdown cells partially restores the aggressive cancer phenotype and cancer stem cell and EMT marker expression. Tumor studies show that rapamycin reduces tumor growth and cancer stem cell marker expression and EMT.These studies suggest that TG2 stimulates mTOR activity to stimulate cancer cell stemness and EMT and drive aggressive tumor growth.cancer stem cells, epidermal squamous cell carcinoma, mTOR, transglutaminase 2 | INTRODUCTIONTransglutaminase 2 (TG2) is a uniquely oncogenic member of the transglutaminase family that is a focus of intense study relating to its role as a cancer cell survival factor. 1,2 TG2 displays transamidase and GTP binding activity, and recent studies show that GTP binding activity is required to maintain the cancer phenotype. 1-4 TG2 level and signaling activity are markedly increased in tumors and tumor cell lines [5][6][7][8][9] where it suppresses expression of tumor suppressor genes, drives synthesis, and deposition of fibronectin and collagen, stabilizes the extracellular matrix and stimulates epithelial-mesenchymal transition (EMT). 4,9,10 Recent studies indicate that TG2 is highly enriched in epidermal cancer stem-like cells (ECS cells) where it stimulates an aggressive cancer phenotype. [2][3][4]11 It localizes in the extra-and intracellular environment where it regulates a host of procancer plasma membrane receptors and intracellular signaling cascades. 3,[11][12][13][14][15] Mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 comprise two distinct functional complexes. mTORC1 (mammalian target of rapamycin [mTOR]) is involved in driving the survival of cancer cells. 16 mTOR is activated in response to nutrient conditions favorable for cell growth and in response to signaling

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Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

Cited by 11 publications

References 24 publications

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition

The transglutaminase 2 cancer cell survival factor maintains mTOR activity to drive an aggressive cancer phenotype

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