Transglutaminase-2 induces N-cadherin expression in TGF-β1-induced epithelial mesenchymal transition via c-Jun-N-terminal kinase activation by protein phosphatase 2A down-regulation

Park, Mi Kyung; You, Hye Jin; Lee, He Ja; Kang, Ju Hee; Oh, Seung Hyun; Kim, Soo Youl; Lee, Chang Hoon

doi:10.1016/j.ejca.2012.11.036

Cited by 40 publications

(44 citation statements)

References 36 publications

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“…and TGFβ1 is in keeping with the work of Park et al [35] which showed that in A549 lung cancer cells, TG2 induced EMT via TGFβ1 with an elevation of N-cadherin expression in these cells [35].…”

Section: Accepted Manuscriptsupporting

confidence: 88%

“…Further evidence that TG2 is responsible for this crosslinking was shown by the finding that addition of exogenous TG2 to the IB3 cells led to polymerisation of the matrix TGFβ1 present. Although we cannot rule out other mechanisms for how TG2 is acting in TGFβ1 signalling, our data so far suggests that its crosslinking into the cell matrix may be one of them [35,36,38,39].…”

Section: Accepted Manuscriptmentioning

confidence: 75%

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A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis

Nyabam

Wang

Thibault

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Cystic fibrosis (CF) is a genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) for which there is no overall effective treatment. Recent work indicates Tissue Transglutaminase (TG2) plays a pivotal intracellular role in proteostasis in CF epithelia and that the pan TG inhibitor cysteamine improves CFTR stability. Here we show TG2 has another role in CF pathology linked with TGFβ1 activation and signalling, induction of Epithelial-Mesenchymal Transition (EMT), CFTR stability and induction of matrix deposition. We show that increased TG2 expression in normal and CF bronchial epithelial cells increases TGFβ1 levels, promoting EMT progression, and impairs tight junctions as measured by Trans Epithelial Electric Resistance (TEER) which can be reversed by selective inhibition of TG2 with an observed increase in CFTR stability. Our data indicate that selective inhibition of TG2 provides a potential therapeutic avenue for reducing fibrosis and increasing CFTR stability in CF.

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Section: Accepted Manuscriptsupporting

confidence: 88%

Section: Accepted Manuscriptmentioning

confidence: 75%

A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis

Nyabam

Wang

Thibault

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…37,38 Consistent with this observation, silencing of TG-2 has been associated with reduced pJNK in malignancies. 37,39,40 Moreover, it has been reported that JNK can localize to paxillin-containing focal adhesions in corneal epithelial cells. 6,12,41 Various studies have shown that pJNK can be a kinase for Ser 178 of paxillin.…”

Section: Hypothesismentioning

confidence: 99%

Transglutaminase-2 in cell adhesion

Png

Tong

2013

Cell Adhesion & Migration

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“…The reasons for these different effects of TG2 on migration are likely due in part to the fact that TG2 plays different roles in a context and cell-type specific manner and is thus likely to be modulating different targets in the various models [5,6]. For example, TG2 has been shown to modulate integrin and MAP kinase pathways in certain cell types, which can control actin dynamics to facilitate cellular migration [11,12]. Other studies have shown that extracellular TG2 may modulate cell migration by acting as an intermediate between the extracellular matrix (ECM; fibronectin) and cell contacts (integrin) [13].…”

Section: Introductionmentioning

confidence: 99%

“…Other studies have shown that extracellular TG2 may modulate cell migration by acting as an intermediate between the extracellular matrix (ECM; fibronectin) and cell contacts (integrin) [13]. Moreover, intracellular TG2 has been shown to interact with JNK and p38, both of which can be activated though the TGFβ receptors and enhance migration [12,14]. In astrocytes, activation of the TGFβ receptors increases astrocyte mobility partly due to activation of integrin and MAP kinase pathway, which modulates their morphology and movement [15].…”

Section: Introductionmentioning

confidence: 99%

Inhibition or ablation of transglutaminase 2 impairs astrocyte migration

Monteagudo

Akbar

et al. 2017

Biochemical and Biophysical Research Communications

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Astrocytes play numerous complex roles that support and facilitate the function of neurons. Further, when there is an injury to the central nervous system (CNS) they can both facilitate or ameliorate functional recovery depending on the location and severity of the injury. When a CNS injury is relatively severe a glial scar is formed, which is primarily composed of astrocytes. The glial scar can be both beneficial, by limiting inflammation, and detrimental, by preventing neuronal projections, to functional recovery. Thus, understanding the processes and proteins that regulate astrocyte migration in response to injury is still of fundamental importance. One protein that is likely involved in astrocyte migration is transglutaminase 2 (TG2); a multifunctional protein expressed ubiquitously throughout the brain. Its functions include transamidation and GTPase activity, among others, and previous studies have implicated TG2 as a regulator of migration. Therefore, we examined the role of TG2 in primary astrocyte migration subsequent to injury. Using wild type or TG2−/− astrocytes, we manipulated the different functions and conformation of TG2 with novel irreversible inhibitors or mutant versions of the protein. Results showed that both inhibition and ablation of TG2 in primary astrocytes significantly inhibit migration. Additionally, we show that the deficiency in migration caused by deletion of TG2 can only be rescued with the native protein and not with mutants. Finally, the addition of TGFβ rescued the migration deficiency independent of TG2. Taken together, our study shows that transamidation and GTP/GDP-binding are necessary for inhibiting astrocyte migration and it is TGFβ independent.

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Transglutaminase-2 induces N-cadherin expression in TGF-β1-induced epithelial mesenchymal transition via c-Jun-N-terminal kinase activation by protein phosphatase 2A down-regulation

Cited by 40 publications

References 36 publications

A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis

A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis

Transglutaminase-2 in cell adhesion

Inhibition or ablation of transglutaminase 2 impairs astrocyte migration

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