Cell-surface-associated tissue transglutaminase is a target of MMP-2 proteolysis

Alexey M. Belkin, Evgeny A. Zemskov, Jun Hang, Sergey Akimov, Sergey Sikora, Alex Y. Strongin

Research output: Contribution to journalArticle

Abstract

MT1-MMP, a prototypic member of a membrane-type metalloproteinase subfamily, is an invasion promoting protease and an activator of MMP-2. In addition, MT1-MMP proteolysis regulates the functionality of cell-surface adhesion/signaling receptors including tissue transglutaminase (tTG). tTG is known to serve as an adhesion coreceptor for β1/β3 integrins and as an enzyme that catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Here, we report that MMP-2, functioning in concert with MT1-MMP, hydrolyzes cell-surface-associated tTG, thereby further promoting the effect initiated by the activator of MMP-2. tTG, in return, preferentially associates with the activation intermediate of MMP-2. This event decreases the rate of MMP-2 maturation and protects tTG against proteolysis by MMP-2. Our cell culture, in vitro experiments, and in silico modeling indicate that the catalytic domain of MMP-2 directly associates with the core enzymatic domain II of tTG (the Kd = 380 nM). The follow-up cleavage of the domain II eliminates both the receptor and the enzymatic activity of tTG. Our data illuminate the coordinated interplay involving the MT1-MMP/MMP-2 protease tandem in the regulation of the cell receptors and explain the underlying biochemical mechanisms of the extensive tTG proteolysis that exists at the normal tissue/tumor boundary. Our findings also suggest that neoplasms, which express functionally active MT1-MMP and, therefore, activate soluble MMP-2, can contribute to the degradation of tTG expressed in neighboring host cells. The loss of adhesive and enzymatic activities of tTG at the interface between tumor and normal tissue will decrease cell-matrix interactions and inhibit matrix cross-linking, causing multiple pathological alterations in host cell adhesion and locomotion.

Original languageEnglish (US)
Pages (from-to)11760-11769
Number of pages10
JournalBiochemistry®
Volume43
Issue number37
DOIs
StatePublished - Sep 21 2004
Externally publishedYes

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Proteolysis
Matrix Metalloproteinases
Matrix Metalloproteinase 14
Cell Adhesion
Tumors
Peptide Hydrolases
Adhesion
transglutaminase 2
Tissue
Neoplasms
Cell adhesion
Polyamines
Metalloproteases
Cell culture
Integrins
Cell Communication
Adhesives
Computer Simulation
Cell Movement
Catalytic Domain

ASJC Scopus subject areas

  • Biochemistry

Cite this

Belkin, A. M., Zemskov, E. A., Hang, J., Akimov, S., Sikora, S., & Strongin, A. Y. (2004). Cell-surface-associated tissue transglutaminase is a target of MMP-2 proteolysis. Biochemistry®, 43(37), 11760-11769. https://doi.org/10.1021/bi049266z

Cell-surface-associated tissue transglutaminase is a target of MMP-2 proteolysis. / Belkin, Alexey M.; Zemskov, Evgeny A.; Hang, Jun; Akimov, Sergey; Sikora, Sergey; Strongin, Alex Y.

In: Biochemistry®, Vol. 43, No. 37, 21.09.2004, p. 11760-11769.

Research output: Contribution to journalArticle

Belkin, AM, Zemskov, EA, Hang, J, Akimov, S, Sikora, S & Strongin, AY 2004, 'Cell-surface-associated tissue transglutaminase is a target of MMP-2 proteolysis', Biochemistry®, vol. 43, no. 37, pp. 11760-11769. https://doi.org/10.1021/bi049266z
Belkin, Alexey M. ; Zemskov, Evgeny A. ; Hang, Jun ; Akimov, Sergey ; Sikora, Sergey ; Strongin, Alex Y. / Cell-surface-associated tissue transglutaminase is a target of MMP-2 proteolysis. In: Biochemistry®. 2004 ; Vol. 43, No. 37. pp. 11760-11769.
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