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Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin.

Akimov SS, Krylov D, Fleischman LF, Belkin AM - J. Cell Biol. (2000)

Bottom Line: These effects are specific for tissue transglutaminase and are not shared by its functional homologue, a catalytic subunit of factor XIII.Adhesive function of tissue transglutaminase does not require its cross-linking activity but depends on its stable noncovalent association with integrins.Transglutaminase interacts directly with multiple integrins of beta1 and beta3 subfamilies, but not with beta2 integrins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, American Red Cross, Rockville, Maryland 20855, USA.

ABSTRACT
The protein cross-linking enzyme tissue transglutaminase binds in vitro with high affinity to fibronectin via its 42-kD gelatin-binding domain. Here we report that cell surface transglutaminase mediates adhesion and spreading of cells on the 42-kD fibronectin fragment, which lacks integrin-binding motifs. Overexpression of tissue transglutaminase increases its amount on the cell surface, enhances adhesion and spreading on fibronectin and its 42-kD fragment, enlarges focal adhesions, and amplifies adhesion-dependent phosphorylation of focal adhesion kinase. These effects are specific for tissue transglutaminase and are not shared by its functional homologue, a catalytic subunit of factor XIII. Adhesive function of tissue transglutaminase does not require its cross-linking activity but depends on its stable noncovalent association with integrins. Transglutaminase interacts directly with multiple integrins of beta1 and beta3 subfamilies, but not with beta2 integrins. Complexes of transglutaminase with integrins are formed inside the cell during biosynthesis and accumulate on the surface and in focal adhesions. Together our results demonstrate that tissue transglutaminase mediates the interaction of integrins with fibronectin, thereby acting as an integrin-associated coreceptor to promote cell adhesion and spreading.

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A model proposing the role of tTG in cell adhesion. Association of integrins with tTG promotes cell adhesion and spreading due to formation of ternary adhesion complexes with Fn. (A) Integrin-mediated adhesion to Fn in the absence of tTG. (B) tTG enhances adhesion acting as a bridge between integrins and Fn. (C) tTG enhances adhesion by mediating the formation of ternary complexes where all three proteins interact with each other.
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Figure 10: A model proposing the role of tTG in cell adhesion. Association of integrins with tTG promotes cell adhesion and spreading due to formation of ternary adhesion complexes with Fn. (A) Integrin-mediated adhesion to Fn in the absence of tTG. (B) tTG enhances adhesion acting as a bridge between integrins and Fn. (C) tTG enhances adhesion by mediating the formation of ternary complexes where all three proteins interact with each other.

Mentions: How does the integrin–tTG interaction promote cell adhesion? Integrins are relatively low affinity receptors for ECM proteins, including Fn. In contrast, tTG binds with high affinity to Fn and its 42-kD fragment (Turner and Lorand 1989; Radek et al. 1993), and as shown here, forms stable complexes with integrins. The presence of integrin-bound tTG on the surface creates a possibility for cells to use an additional binding site within Fn for the interaction with integrins. This potentially doubles the number of sites in the Fn matrix that cells can access in the process of adhesion and spreading. If the Fn chains are fully extended, as in the case of the fibrillar matrix (Dzamba and Peters 1991), the tTG-binding site would be separated from the RGD motif by >20 nm, minimizing steric restrictions against their simultaneous occupation. Furthermore, the tTG-binding site on integrins most likely involves sequences outside the integrin ligand-binding pocket, consistent with the fact that their association is not perturbed by 110-kD cell-binding Fn fragment or RGD-containing peptides and function-blocking anti–β1 integrin antibodies (data not shown). Therefore, two types of ternary adhesion complexes can be envisioned as shown schematically in Fig. 10. Cells can adhere to Fn via integrins in the absence of tTG (Fig. 10 A). In the simplest case, tTG serves merely as a bridge between integrin and Fn (Fig. 10 B). This alone could strengthen adhesion because of the higher affinity and by allowing a second integrin molecule to access the RGD site in the same Fn chain. However, beyond this is the possibility for even more stable ternary complexes, where each protein interacts with two others (Fig. 10 C). Either scenario should increase cell adhesion and spreading on Fn. In agreement with the proposed model, tTG promotes integrin clustering in the membrane, and consequently, amplifies integrin outside-in signaling (Fig. 9). Integrin clustering could be further facilitated if tTG forms stable bivalent dimers, as does its homologue in FXIIIa (Yee et al. 1994). It is also possible that binding to tTG could affect the activation state of integrins.


Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin.

Akimov SS, Krylov D, Fleischman LF, Belkin AM - J. Cell Biol. (2000)

A model proposing the role of tTG in cell adhesion. Association of integrins with tTG promotes cell adhesion and spreading due to formation of ternary adhesion complexes with Fn. (A) Integrin-mediated adhesion to Fn in the absence of tTG. (B) tTG enhances adhesion acting as a bridge between integrins and Fn. (C) tTG enhances adhesion by mediating the formation of ternary complexes where all three proteins interact with each other.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169362&req=5

Figure 10: A model proposing the role of tTG in cell adhesion. Association of integrins with tTG promotes cell adhesion and spreading due to formation of ternary adhesion complexes with Fn. (A) Integrin-mediated adhesion to Fn in the absence of tTG. (B) tTG enhances adhesion acting as a bridge between integrins and Fn. (C) tTG enhances adhesion by mediating the formation of ternary complexes where all three proteins interact with each other.
Mentions: How does the integrin–tTG interaction promote cell adhesion? Integrins are relatively low affinity receptors for ECM proteins, including Fn. In contrast, tTG binds with high affinity to Fn and its 42-kD fragment (Turner and Lorand 1989; Radek et al. 1993), and as shown here, forms stable complexes with integrins. The presence of integrin-bound tTG on the surface creates a possibility for cells to use an additional binding site within Fn for the interaction with integrins. This potentially doubles the number of sites in the Fn matrix that cells can access in the process of adhesion and spreading. If the Fn chains are fully extended, as in the case of the fibrillar matrix (Dzamba and Peters 1991), the tTG-binding site would be separated from the RGD motif by >20 nm, minimizing steric restrictions against their simultaneous occupation. Furthermore, the tTG-binding site on integrins most likely involves sequences outside the integrin ligand-binding pocket, consistent with the fact that their association is not perturbed by 110-kD cell-binding Fn fragment or RGD-containing peptides and function-blocking anti–β1 integrin antibodies (data not shown). Therefore, two types of ternary adhesion complexes can be envisioned as shown schematically in Fig. 10. Cells can adhere to Fn via integrins in the absence of tTG (Fig. 10 A). In the simplest case, tTG serves merely as a bridge between integrin and Fn (Fig. 10 B). This alone could strengthen adhesion because of the higher affinity and by allowing a second integrin molecule to access the RGD site in the same Fn chain. However, beyond this is the possibility for even more stable ternary complexes, where each protein interacts with two others (Fig. 10 C). Either scenario should increase cell adhesion and spreading on Fn. In agreement with the proposed model, tTG promotes integrin clustering in the membrane, and consequently, amplifies integrin outside-in signaling (Fig. 9). Integrin clustering could be further facilitated if tTG forms stable bivalent dimers, as does its homologue in FXIIIa (Yee et al. 1994). It is also possible that binding to tTG could affect the activation state of integrins.

Bottom Line: These effects are specific for tissue transglutaminase and are not shared by its functional homologue, a catalytic subunit of factor XIII.Adhesive function of tissue transglutaminase does not require its cross-linking activity but depends on its stable noncovalent association with integrins.Transglutaminase interacts directly with multiple integrins of beta1 and beta3 subfamilies, but not with beta2 integrins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, American Red Cross, Rockville, Maryland 20855, USA.

ABSTRACT
The protein cross-linking enzyme tissue transglutaminase binds in vitro with high affinity to fibronectin via its 42-kD gelatin-binding domain. Here we report that cell surface transglutaminase mediates adhesion and spreading of cells on the 42-kD fibronectin fragment, which lacks integrin-binding motifs. Overexpression of tissue transglutaminase increases its amount on the cell surface, enhances adhesion and spreading on fibronectin and its 42-kD fragment, enlarges focal adhesions, and amplifies adhesion-dependent phosphorylation of focal adhesion kinase. These effects are specific for tissue transglutaminase and are not shared by its functional homologue, a catalytic subunit of factor XIII. Adhesive function of tissue transglutaminase does not require its cross-linking activity but depends on its stable noncovalent association with integrins. Transglutaminase interacts directly with multiple integrins of beta1 and beta3 subfamilies, but not with beta2 integrins. Complexes of transglutaminase with integrins are formed inside the cell during biosynthesis and accumulate on the surface and in focal adhesions. Together our results demonstrate that tissue transglutaminase mediates the interaction of integrins with fibronectin, thereby acting as an integrin-associated coreceptor to promote cell adhesion and spreading.

Show MeSH
Related in: MedlinePlus