A Novel RGD-independent Cell Adhesion Pathway Mediated by Fibronectin-bound Tissue Transglutaminase Rescues Cells from Anoikis

Verderio, Elisabetta; Telci, Dilek; Okoye, Afam A.; Melino, Gerry; Griffin, Martin

doi:10.1074/jbc.m303303200

Cited by 135 publications

(184 citation statements)

References 48 publications

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“…TG2 was shown to bind to extracellular matrix components and also to β1-and β3-integrins or other cell surface receptors or co-receptors such as platelet-derived growth factor receptor (PDGFR) or syndecan-4 on the cell surface, enhancing cell adhesion [27,[38][39][40]. Interestingly, some of the ECM-related TG2 functions are independent of enzyme activity [5,41].…”

Section: Discussionmentioning

confidence: 99%

“…Fibronectin is a well-known glutamine donor substrate of TG2 and their interaction plays a role in adhesion of cancer cells [27]. Since S100A4 also exhibits extracellular functions, we studied the effect of the presence of both TG2 and S100A4 in ECM on the adhesion of A431 epithelial carcinoma cells.…”

Section: S100a4 and Tg2 Cooperate In Enhancing Cancer Cell Adhesionmentioning

confidence: 99%

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Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2

Biri

Kiss

Király

et al. 2015

Biochemical Journal

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Transglutaminase-2 (TG2) is best known as a Ca 2+ -dependent cross-linking enzyme; however, some of its extracellular matrix-related functions are independent from its catalytic activity and include matrix remodeling, adhesion and migration. S100A4 belongs to the Ca 2+ -binding EF-hand S100 protein family and acts both intra-and extracellularly through binding to various partners. It regulates cell migration and its overexpression is strongly associated with metastasis and poor survival in various cancers. TG2 has recently been suggested to mediate S100A4-dependent tumor cell migration. Here we provide evidence that S100A4 is an interacting partner and also specific amine donor of TG2. TG2 incorporates a glutamine donor peptide to Lys100 in the C-terminal random coil region of S100A4. Importantly, the enzyme activity is not necessary for the interaction: S100A4 also binds to TG2 in the presence of a specific inhibitor that keeps the enzyme in an open conformation, or to an enzymatically inactive mutant. We also found that S100A4 considerably enhances TG2-mediated adhesion of A431 epithelial carcinoma cells to the extracellular matrix. This role is independent of enzyme activity and requires the open conformation of TG2. We propose that S100A4 stabilizes the open conformation of TG2, which binds to its cell surface receptor in this state and increases cell adhesion.Summary: S100A4 and transglutaminase-2 have a role in metastasis. S100A4 is an interaction partner and specific amine substrate of transglutaminase-2, promoting its open conformation and leading to enhanced cell adhesion. Studying their interaction could contribute to the better understanding of metastasis.Running title: S100A4: substrate and binding partner of transglutaminase-2

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Section: Discussionmentioning

confidence: 99%

Section: S100a4 and Tg2 Cooperate In Enhancing Cancer Cell Adhesionmentioning

confidence: 99%

Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2

Biri

Kiss

Király

et al. 2015

Biochemical Journal

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“…Our studies clearly indicate that FAK is not required for the inducible activation of AKT in response to TGF-β1 stimulation; this may be related to a mechanism whereby soluble autocrine factor(s) secreted in a p38 MAPKdependent and SMAD3-independent manner are capable of activating the PI3K-AKT pathway [8]. Interestingly, blockade of the PI3K-AKT pathway did not completely inhibit anoikisresistance conferred by TGF-β1, suggesting that the participation of non-AKT and non-FAK pathways may also contribute to the anoikis-resistant phenotype [43]; alternatively, the additional protection may be attributed to the relatively small, but significant, increases in FAK activity observed in cells treated with TGF-β1 despite the presence of RGD-containing peptides.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Horowitz

Rogers

Sharma

et al. 2007

Cellular Signalling

224

177

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Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/antiapoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these prosurvival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.

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“…After TG2 translocates to the ECM, it functions in a high Ca 2 þ environment that enhances its ability to act as a crosslinking transamidase and stabilize the ECM from mechanical and proteolytic degradation (Aeschlimann and Thomazy, 2000). The association of TG2 with fibronectin in the ECM results in the formation of TG2-fibronectin complexes with pro-survival characteristics (Verderio et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

et al. 2006

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Transglutaminase 2 (TG2, a.k.a. tissue transglutaminase) belongs to a family of transglutaminase enzymes that stabilize proteins by affecting covalent crosslinking via formation of amide bonds. Cell surface TG2 is directly involved as an adhesive receptor in cell-extracellular matrix (ECM) interactions. Here, we show that TG2 activity is elevated in glioblastomas compared with non-neoplastic brain. Immunofluorescent studies showed increased staining of fibronectin colocalized with TG2 in the ECM in glioblastomas. In addition, small clusters of invading human glioblastoma cells present in non-neoplastic brain parenchyma secrete high levels of TG2 and fibronectin that distinguish them from normal brain stroma. Downregulation of TG2 in U87MG glioblastoma cells with RNAi demonstrated decreased assembly of fibronectin in the ECM. Treatment with KCC009 blocked the remodeling of fibronectin in the ECM in glioblastomas in both in vitro and in vivo studies. KCC009 treatment in mice harboring orthotopic glioblastomas (DBT-FG) sensitized the tumors to N,N 0 -bis(2-chloroethyl)-N-nitrosourea chemotherapy, as measured by reduced bioluminescence, increased apoptosis and prolonged survival. The ability of KCC009 to interfere with the permissive remodeling of fibronectin in the ECM in glioblastomas suggests a novel target to enhance sensitivity to chemotherapy directed not only at the tumor mass, but also invading glioblastoma cells.

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A Novel RGD-independent Cell Adhesion Pathway Mediated by Fibronectin-bound Tissue Transglutaminase Rescues Cells from Anoikis

Cited by 135 publications

References 48 publications

Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2

Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

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