LDL Receptor-Related Protein as a Component of the Midkine Receptor

Muramatsu, Hisako; Zou, Kun; Sakaguchi, Nahoko; Ikematsu, Shinya; Sakuma, Sadatoshi; Muramatsu, Takashi

doi:10.1006/bbrc.2000.2549

Cited by 144 publications

(117 citation statements)

References 50 publications

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“…Although we cannot rule that Mdk simply acts through modulating the well-known effects of heparin on bone cells, there are several in vitro studies demonstrating binding of Mdk and Ptn to specific membrane proteins, such as syndecans, integrins, low-density lipoprotein receptor-related proteins, the receptor tyrosine kinase ALK, or the receptor tyrosine phosphatase Rptpz. (4,(56)(57)(58)(59)(60)(61)(62)(63)(64)(65) Interestingly, we have observed previously that the expressions of both syndecan-3 and Rptpz increase in the course of osteoblast differentiation and that mice lacking Rptpz display a skeletal phenotype. (27,29) However, since the deficiency of Rptpz resulted in low bone mass, and since Rptpz-deficient calvarial osteoblasts, unlike Mdk-deficient cultures, displayed a marked increase in their proliferation rate, we would assume that Mdk regulates bone formation by other mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Increased trabecular bone formation in mice lacking the growth factor midkine

Neunaber

Catalá-Lehnen

Beil

et al. 2010

Journal of Bone and Mineral Research

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Midkine (Mdk) and pleiotrophin (Ptn) comprise a family of heparin-binding growth factors known primarily for their effects on neuronal cells. Since transgenic mice overexpressing Ptn have been reported to display increased bone density, we have previously analyzed Ptndeficient mice but failed to detect any abnormality of skeletal development and remodeling. Together with the finding that Mdk expression increases in the course of primary osteoblast differentiation, we reasoned that Mdk, rather than Ptn, could play a physiologic role in bone formation. Here, we show that Mdk-deficient mice display an increased trabecular bone volume at 12 and 18 months of age, accompanied by cortical porosity. Histomorphometric quantification demonstrated an increased bone-formation rate compared with wild-type littermates, whereas bone resorption was differentially affected in trabecular and cortical bone of Mdk-deficient mice. To understand the effect of Mdk on bone formation at the molecular level, we performed a genome-wide expression analysis of primary osteoblasts and identified Ank and Enpp1 as Mdk-induced genes whose decreased expression in Mdk-deficient osteoblasts may explain, at least in part, the observed skeletal phenotype. Finally, we performed ovariectomy and observed bone loss only in wild-type but not in Mdk-deficient animals. Taken together, our data demonstrate that Mdk deficiency, at least in mice, results in an increased trabecular bone formation, thereby raising the possibility that Mdk-specific antagonists might prove beneficial in osteoporosis therapy. ß

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Section: Discussionmentioning

confidence: 99%

Increased trabecular bone formation in mice lacking the growth factor midkine

Neunaber

Catalá-Lehnen

Beil

et al. 2010

Journal of Bone and Mineral Research

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“…Statistical analysis is summarised in Table 2. Table 3. kinase, and LDL receptor-related protein (LRP) were recently identified as MK receptors (Maeda et al, 1999;Muramatsu et al, 2000;Stoica et al, 2002). Although it has not been elucidated yet whether or not these receptors form complexes for MK signalling, each protein serves as a receptor transducing intracellular signals for midkine.…”

Section: Discussionmentioning

confidence: 99%

Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

et al. 2003

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The heparin-binding growth factor midkine (MK) is the product of a retinoic acid-responsive gene, and is implicated in neuronal survival and differentiation, and carcinogenesis. We previously reported that MK mRNA expression is elevated in neuroblastoma specimens at all stages, whereas pleiotrophin, the other member of the MK family, is expressed at high levels in favourable neuroblastomas. As MK is a secretory protein, it can be detected in the blood. Here, we show a significant correlation of the plasma MK level with prognostic factors of neuroblastomas. The plasma MK level was determined in 220 patients with neuroblastomas, and compared with that in children without malignant tumors (n ¼ 17, o500 pg ml À1 ). The plasma MK level became significantly elevated with advancing stages (stage 1: 445 pg ml À1 (median), n ¼ 73; stage 2: 589, n ¼ 39; stage 3: 864, n ¼ 40; stage 4: 1445, n ¼ 56; and stage 4S: 2439, n ¼ 12). More importantly, a higher MK level was strongly correlated with poor prognostic factors: over 1 year of age (P ¼ 0.0299), MYCN amplification (Po0.0001), low TrkA expression (P ¼ 0.0005), nonmass screening, sporadic neuroblastomas (Po0.0001), and diploidy/tetraploidy (P ¼ 0.0007). Thus, these results demonstrate that the plasma MK level is a good marker for evaluating the progression of neuroblastomas. Moreover, considering the ability of antisense MK oligodeoxyribonucleotide to suppress tumour growth of colorectal carcinoma cells in nude mice, as recently reported, the present study suggests that MK is a possible candidate molecular target for therapy for neuroblastomas.

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“…LRP1 is a receptor for MK and is required for MK-mediated cell survival (21,22). Because MK and LRP1 are produced simultaneously in most cancer cell lines, this ligand and receptor are produced in the same secretory pathway.…”

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confidence: 99%

Premature Ligand-Receptor Interaction during Biosynthesis Limits the Production of Growth Factor Midkine and Its Receptor LDL Receptor-related Protein 1

Sakamoto¹,

Chen³

et al. 2011

Journal of Biological Chemistry

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Protein production within the secretory pathway is accomplished by complex but organized processes. Here, we demonstrate that the growth factor midkine interacts with LDL receptor-related protein 1 (LRP1) at high affinity (K d value, 2.7 nM) not only at the cell surface but also within the secretory pathway during biosynthesis. The latter premature ligand-receptor interaction resulted in aggregate formation and consequently suppressed midkine secretion and LRP1 maturation. We utilized an endoplasmic reticulum (ER) retrieval signal and an LRP1 fragment, which strongly bound to midkine and the LRP1-specialized chaperone receptor-associated protein (RAP), to construct an ER trapper. The ER trapper efficiently trapped midkine and RAP and mimicked the premature ligand-receptor interaction, i.e. suppressed maturation of the ligand and receptor. The ER trapper also diminished the inhibitory function of LRP1 on platelet-derived growth factor-mediated cell migration. Complementary to these results, an increased expression of RAP was closely associated with midkine expression in human colorectal carcinomas (33 of 39 cases examined). Our results suggest that the premature ligand-receptor interaction plays a role in protein production within the secretory pathway.

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LDL Receptor-Related Protein as a Component of the Midkine Receptor

Cited by 144 publications

References 50 publications

Increased trabecular bone formation in mice lacking the growth factor midkine

Increased trabecular bone formation in mice lacking the growth factor midkine

Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

Premature Ligand-Receptor Interaction during Biosynthesis Limits the Production of Growth Factor Midkine and Its Receptor LDL Receptor-related Protein 1

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