Dimerization of Midkine by Tissue Transglutaminase and Its Functional Implication

Midkine (MK), a retinoic acid-inducible growth/differentiation factor, serves as a substrate for tissue transglutaminase (Kojima, S., Muramatsu, H., Amanuma, H., and Muramatsu, T. 1995. J. Biol. Chem. 270, 9590-9596). Upon incubation with transglutaminase MK forms multimers through cross-linkages. H...

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Bibliographic Details
Published in:The Journal of biological chemistry 1997-04, Vol.272 (14), p.9410-9416
Main Authors: Kojima, S, Inui, T, Muramatsu, H, Suzuki, Y, Kadomatsu, K, Yoshizawa, M, Hirose, S, Kimura, T, Sakakibara, S, Muramatsu, T
Format: Article
Language:English
Subjects:
Animals
Antibodies
Carrier Proteins - metabolism
Cattle
Cytokines - metabolism
Endothelium, Vascular - metabolism
Glutamine
Heparin - metabolism
Humans
Midkine
Protein Conformation
Putrescine - metabolism
Rabbits
Transglutaminases - metabolism
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Summary:Midkine (MK), a retinoic acid-inducible growth/differentiation factor, serves as a substrate for tissue transglutaminase (Kojima, S., Muramatsu, H., Amanuma, H., and Muramatsu, T. 1995. J. Biol. Chem. 270, 9590-9596). Upon incubation with transglutaminase MK forms multimers through cross-linkages. Here, we report the following results. 1) Heparin potentiated the multimer formation by MK. 2) The N- and C-terminal half domains each formed a dimer through the action of transglutaminase. 3) Gln 42 or Gln 44 in the N-terminal half and Gln 95 in the C-terminal half served as amine acceptors in the cross-linking reaction, as judged from the incorporation of putrescine into whole MK or each half domain, and the competitive inhibition of the cross-linking by MK-derived peptides containing Gln residue(s). The strongest inhibition was obtained with Ala 41 -Pro 51 . 4) This peptide abolished the biological activity of MK to enhance the plasminogen activator activity in bovine aortic endothelial cells. The inhibition was limited against the MK monomer, and not seen against the MK dimer, separated by gel filtration chromatography. These results suggest that dimer formation through transglutaminase-mediated cross-linking is an important step as to the biological activity of MK.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.272.14.9410