Identification of Heparin-Binding Sites in Midkine and Their Role in Neurite-Promotion

Asai, Toshinobu; Watanabe, Kiichi; Ichihara-Tanaka, Keiko; Kaneda, Norio; Kojima, Soichi; Iguchi, Akihisa; Inagaki, Fuyuhiko; Muramatsu, Takashi

doi:10.1006/bbrc.1997.6905

Cited by 41 publications

(37 citation statements)

References 36 publications

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“…Here, the C-terminal half of midkine was revealed to be sufficient for the binding. The C-terminal half domain of midkine exhibits various activities: strong heparin-binding activity, neurite promoting activity, and tissue plasminogen activator enhancing activity (21,22). On the other hand, specific functions have not been found for the N-terminal half of midkine, although it weakly binds to heparin (21, 22, 26).…”

Section: Discussionmentioning

confidence: 99%

“…The N-and C-terminal half domains of human midkine (1-59 and 60 -121, respectively) were synthesized as described previously (25). Mouse midkine mutants, R78Q, K83Q, K84Q, K83Q/ K84Q and R78Q/K83Q/K84Q were prepared by site-directed mutagenesis (21,22). Mutations are indicated by the amino acid residues (in one-letter code) in the wild-type and the mutant, preceding and following the numbers of the altered residues, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Midkine has two clusters of basic amino acids (Clusters I and II) located at the surface on one side of the C-terminal half domain, which are considered to be heparin binding sites (23 Five mouse midkine mutants were prepared, in which some of the basic amino acids in the Cluster I and/or II were changed to glutamine: R78Q, K83Q, K84Q, K83Q/K84Q, and R78Q/ K83Q/K84Q (21,22). As shown in Fig.…”

Section: Binding Of Ptp-s Tomentioning

confidence: 99%

“…The C-terminal half of midkine binds strongly to heparin and exhibits neurite outgrowth-promoting and plasminogen activator-enhancing activities (21,22). On the other hand, the N-terminal half of midkine, which shows relatively weak heparin binding activity, does not promote neurite outgrowth or enhance plasminogen activator activity (21,22). NMR spectroscopy revealed two clusters of basic amino acids in the C-terminal half of midkine, Clusters I and II, both of which interact with heparin oligosaccharides (23).…”

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confidence: 99%

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A Receptor-like Protein-tyrosine Phosphatase PTPζ/RPTPβ Binds a Heparin-binding Growth Factor Midkine

Maeda¹,

Ichihara-Tanaka²,

Kimura³

et al. 1999

Journal of Biological Chemistry

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278

208

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Midkine is a 13-kDa heparin-binding growth factor with 45% sequence identity to pleiotrophin. Pleiotrophin has been demonstrated to bind to protein-tyrosine phosphatase (PTP ) with high affinity. In this study, we examined the binding of midkine to PTP by solidphase binding assay. Midkine and pleiotrophin binding to PTP were equally inhibited by soluble pleiotrophin and also by some specific glycosaminoglycans. For both bindings, Scatchard analysis revealed low (3.0 nM) and high (0.58 nM) affinity binding sites. These results suggested that PTP is a common receptor for midkine and pleiotrophin. Midkine is structurally divided into the Nand C-terminal halves, and the latter exhibited full activity for PTP binding and neuronal migration induction. The C-terminal half contains two heparin-binding sites consisting of clusters of basic amino acids, Clusters I and II. A mutation at Arg 78 in Cluster I resulted in loss of the high affinity binding and reduced neuronal migration-inducing activity, while mutations at Lys 83 and Lys 84 in Cluster II showed almost no effect on either activity. Chondroitinase ABC-treated PTP exhibited similar low affinity binding both to the native midkine and midkine mutants at Arg 78 . These results suggested that Arg 78 in midkine plays an essential role in high affinity binding to PTP by interacting with the chondroitin sulfate portion of this receptor.PTP /RPTP␤ 1 is a receptor-like protein-tyrosine phosphatase, which is abundantly expressed in the central nervous system as a chondroitin sulfate proteoglycan (1-4). PTP is composed of an N-terminal carbonic anhydrase-like domain, a fibronectin type III domain, a serine, glycine-rich domain that is thought to be chondroitin sulfate attachment region, a transmembrane segment, and two tyrosine phosphatase domains (1, 2). There are three splice variants of this molecule: (a) the full-length PTP (PTP -A); (b) the short form of PTP , in which most of the serine, glycine-rich region is deleted (PTP -B); and (c) the secreted form (PTP -S), which corresponds to the extracellular region of PTP -A and is also known as 6B4 proteoglycan/phosphacan (3, 5). All these splice variants are expressed as chondroitin sulfate proteoglycans in the brain (6), suggesting that chondroitin sulfate plays an essential role in receptor function.Several proteins such as contactin, tenascin, L1, NCAM, and TAG1 have been reported to bind PTP (7-9). Contactin is thought to be a neuronal receptor of PTP expressed on glial cells (7). Recently, we found that PTP binds with pleiotrophin/ heparin-binding growth-associated molecule (10), in that a chondroitin sulfate portion of PTP constitutes a part of the pleiotrophin binding site and regulates the affinity of PTPpleiotrophin binding (10). We further demonstrated that pleiotrophin-induced neurite outgrowth and neuronal migration were suppressed by chondroitin sulfate, polyclonal antibodies against the extracellular domain of PTP , and sodium vanadate, a protein-tyrosine phosphatase inhibitor. These findings suggested that P...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Binding Of Ptp-s Tomentioning

confidence: 99%

mentioning

confidence: 99%

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A Receptor-like Protein-tyrosine Phosphatase PTPζ/RPTPβ Binds a Heparin-binding Growth Factor Midkine

Maeda¹,

Ichihara-Tanaka²,

Kimura³

et al. 1999

Journal of Biological Chemistry

Self Cite

278

208

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“…34) The mutation assays of MK as well indicate that the C-terminal domain is important for its biological activity while the N-terminal domain plays a role in maintaining structural stability. 35,36) The soluble structure of PTN resolved by MRI was similar to MK and the binding of heparin similarly occurs at the β-sheet domains. This heparin-binding site is homologous with the thrombospondin type-I repeat (TSR-I) motif which is found in various extracellular proteins that mediate cell-to-extracellular matrix and cell-to-cell interactions.…”

Section: Reviewmentioning

confidence: 80%

Functional Receptors and Intracellular Signal Pathways of Midkine (MK) and Pleiotrophin (PTN)

Zhu

et al. 2014

Biological & Pharmaceutical Bulletin

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BIFUNCTIONAL EFFECTS OF HEPARIN‐BINDING PROTEIN HBp17 ON DNA SYNTHESIS IN CELLS

Chen

Wang

Sato

2001

Cell Biology International

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A 17 kD heparin-binding protein (HBp17) has a biphasic dose-dependent effect on DNA synthesis in 3T3 cells. Maximal stimulation of DNA synthesis occurs at 8 ng/ml HBp17, but a half-maximal inhibition occurs at approximately 500 ng/ml. This inhibition can easily be reversed by addition of 400 pg/ml aFGF or 100 pg/ml bFGF, whereas EGF had no effect. This biphasic action of HBp17 was also seen in human umbilical vein endothelial cells (HUVEC), whereas it was not found in the malignant cell line, A431-AJC. The functional relationship between HBp17 and FGF is discussed.

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Identification of Heparin-Binding Sites in Midkine and Their Role in Neurite-Promotion

Cited by 41 publications

References 36 publications

A Receptor-like Protein-tyrosine Phosphatase PTPζ/RPTPβ Binds a Heparin-binding Growth Factor Midkine

A Receptor-like Protein-tyrosine Phosphatase PTPζ/RPTPβ Binds a Heparin-binding Growth Factor Midkine

Functional Receptors and Intracellular Signal Pathways of Midkine (MK) and Pleiotrophin (PTN)

BIFUNCTIONAL EFFECTS OF HEPARIN‐BINDING PROTEIN HBp17 ON DNA SYNTHESIS IN CELLS

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