Transglutaminase Forms Midkine Homodimers in Cerebellar Neurons and Modulates the Neurite-Outgrowth Response

Mahoney, Sally-Ann; Perry, Michael J.; Seddon, Andrew P.; Bőhlen, Peter; Haynes, Laurence W.

doi:10.1006/bbrc.1996.0998

Cited by 37 publications

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“…cerebellar cortex, PTP, pleiotrophin and D unit-rich CS were accumulated in the molecular layer, and it has been considered that these molecules cooperatively played roles in the dendrite formation of Purkinje cells (32,33). Transglutaminase type 2 was also reported to be expressed in the molecular layer (12), suggesting that these components constitute the extracellular signaling complex involved in the development of Purkinje cell dendrites.…”

Section: Fractionmentioning

confidence: 99%

“…Furthermore, both growth factors were cross-linked by transglutaminases forming covalently bound multimers (12)(13)(14)(15), and this multimerization process was remarkably promoted by heparin and CS (13,15). These observations raise the possibility that multimers of pleiotrophin and midkine bind with PTP through CS inducing the dimerization of this receptor.…”

mentioning

confidence: 96%

“…On the other hand, midkine and pleiotrophin easily formed noncovalently bound multimers, and it has been suggested that multimers larger than dimers are the active forms (12)(13)(14)(15). Furthermore, both growth factors were cross-linked by transglutaminases forming covalently bound multimers (12)(13)(14)(15), and this multimerization process was remarkably promoted by heparin and CS (13,15).…”

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confidence: 99%

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The Binding of Chondroitin Sulfate to Pleiotrophin/Heparin-binding Growth-associated Molecule Is Regulated by Chain Length and Oversulfated Structures

Maeda

Fukazawa

Hata

2006

Journal of Biological Chemistry

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Pleiotrophin is an 18-kDa heparin-binding growth factor, which uses chondroitin sulfate (CS) proteoglycan, PTP as a receptor. It has been suggested that the D-type structure (GlcA(2S)␤1-3GalNAc(6S)) in CS contributes to the high affinity binding between PTP and pleiotrophin. Here, we analyzed the interaction of shark cartilage CS-D with pleiotrophin using a surface plasmon resonance biosensor to reveal the importance of D-type structure. CS-D was partially digested with chondroitinase ABC, and fractionated using a Superdex 75pg column. The >18-mer CS fractions showed significant binding to pleiotrophin, and the longer fractions had stronger affinity for pleiotrophin than the shorter ones. The ϳ46-mer CS fraction bound to densely immobilized pleiotrophin with high affinity (K D ‫؍‬ ϳ30 nM), and the binding reactions fitted the bivalent analyte model. However, when the density of the immobilized pleiotrophin was lowered, the strength of affinity remarkably decreased (K D ‫؍‬ ϳ2.5 M), and the reactions no longer fitted the model and were considered to be monovalent binding. The 20ϳ24-mer fractions showed low affinity binding to densely immobilized pleiotrophin (K D ‫؍‬ 3ϳ20 M), which seemed to be monovalent. When ϳ22-mer CS oligosaccharides were fractionated by strong anion exchange HPLC, each fraction differed in affinity for pleiotrophin (K D ‫؍‬ 0.36 ϳ >10 M), and the affinity correlated with the amounts of D-and E-(GlcA␤1-3GalNAc(4S,6S)) type oversulfated structures. These results suggest that the binding of pleiotrophin to CS is regulated by multivalency with CS ϳ20 mer as a unit and by the amounts of oversulfated structures.Pleiotrophin, also known as heparin-binding growth-associated molecule (HB-GAM) 2 or heparin affin regulatory peptide (HARP), is an 18-kDa growth factor that shows 45% amino acid sequence identity with midkine (1, 2). Pleiotrophin and midkine share many biological activities such as the promotion of neurite outgrowth and migration of embryonic neurons and osteoblasts (1, 2). Furthermore, it has been revealed that both use a common signal-transducing receptor, receptortype protein-tyrosine phosphatase (PTP) (3-7). PTP is synthesized as a membrane-bound chondroitin sulfate (CS) proteoglycan, and its extracellular variant, which is generated by alternative splicing, is secreted as a major soluble CS proteoglycan in the brain, phosphacan (8, 9).The binding of phosphacan to pleiotrophin and midkine depends on the CS portion of this proteoglycan, and the removal of CS resulted in a remarkable decrease in the binding affinity (9, 10). It was revealed that pleiotrophin inactivated the tyrosine phosphatase activity of this receptor leading to an increase in the tyrosine phosphorylation levels of specific substrates such as cat-1 and ␤-catenin (4, 11). Several researchers suggested that pleiotrophin induces the dimerization of PTP, which results in the inactivation of its enzymatic activity (4, 11).On the other hand, midkine and pleiotrophin easily formed noncovalently bound multimers, and it has be...

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Section: Fractionmentioning

confidence: 99%

mentioning

confidence: 96%

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confidence: 99%

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The Binding of Chondroitin Sulfate to Pleiotrophin/Heparin-binding Growth-associated Molecule Is Regulated by Chain Length and Oversulfated Structures

Maeda

Fukazawa

Hata

2006

Journal of Biological Chemistry

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“…Requirement of the Cross-linking of MK for Enhancement of the PA Level-Next, we examined whether or not the crosslinking of MK participated in the MK action of enhancing the PA level, using a Gln-containing peptide, Ala 41 -Pro 51 , that showed the strongest inhibition against the cross-linking reaction (Figs. 5 and 7).…”

Section: Enhancement Of the Cross-linking Of Mk Bymentioning

confidence: 99%

“…Prior to this discovery, a 29-kDa MKrelated protein, which is now recognized as a dimer of MK, had been detected in a variety of tissues, such as the lymphonode, spleen, testis, small intestine, stomach, lung, kidney, and liver (39). Furthermore, Haynes and colleagues (40,41) reported similar dimer formation by MK in the developing brain. These lines of accumulating evidence suggest that the cross-linking of MK by tissue transglutaminase may occur and play an important role in MK biology in vivo.…”

mentioning

confidence: 99%

Dimerization of Midkine by Tissue Transglutaminase and Its Functional Implication

Kojima¹,

Inui

Muramatsu

et al. 1997

Journal of Biological Chemistry

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Effects and Analysis of Transglutamination on Protein Aggregation and Clearance in Neurodegenerative Diseases

Nemes

2011

Advances in Enzymology - And Related Areas of Molecular Biology

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Transglutaminase Forms Midkine Homodimers in Cerebellar Neurons and Modulates the Neurite-Outgrowth Response

Cited by 37 publications

References 0 publications

The Binding of Chondroitin Sulfate to Pleiotrophin/Heparin-binding Growth-associated Molecule Is Regulated by Chain Length and Oversulfated Structures

The Binding of Chondroitin Sulfate to Pleiotrophin/Heparin-binding Growth-associated Molecule Is Regulated by Chain Length and Oversulfated Structures

Dimerization of Midkine by Tissue Transglutaminase and Its Functional Implication

Effects and Analysis of Transglutamination on Protein Aggregation and Clearance in Neurodegenerative Diseases

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