Midkine Binds to Anaplastic Lymphoma Kinase (ALK) and Acts as a Growth Factor for Different Cell Types

Stoica, Gerald E.; Kuo, Angera H.; Powers, Ciaran; Bowden, Emma T.; Sale, Elaine Buchert; Riegel, Anna T.; Wellstein, Anton

doi:10.1074/jbc.m205749200

Cited by 304 publications

(281 citation statements)

References 62 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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“…Finally, domains that promote spontaneous dimerization are part of the NPM-ALK fusion protein and are not present in the full-length ALK. Understanding the mechanisms of the full-length ALK is important because of the growing evidence that full-length ALK expression is frequently expressed in human carcinomas (Lawrence et al, 2000;Powers et al, 2002;Stoica et al, 2002;Li et al, 2004;Osajima-Hakomori et al, 2005). We have recently identified ALK as a receptor for PTN and MK (Stoica et al, 2001.…”

Section: Discussionmentioning

confidence: 99%

“…Full-length ALK was initially described as an orphan receptor tyrosine kinase that shows restricted tissue distribution and is regulated during organ development (Iwahara et al, 1997;Morris et al, 1997). Several studies show expression of full-length ALK protein in cultured fibroblasts and endothelial cells as well as cell lines derived from epithelial cancers such as pancreatic and breast carcinoma (Stoica et al, 2001 and the neuroectoderm, that is, melanoma (Dirks et al, 2002), neuroblastoma Stoica et al, 2002) glioblastoma and non-Hodgkin's lymphoma (Delsol et al, 1997), reviewed by Pulford et al (2004).…”

Section: Introductionmentioning

confidence: 99%

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

et al. 2006

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Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase in the insulin receptor superfamily. We recently demonstrated that the growth factors pleiotrophin (PTN) and midkine (MK) are ligands for ALK and that upon ALK activation, insulin receptor substrate-1 (IRS-1) and other substrates are phosphorylated. Here, the role of IRS-1 in ligand-mediated ALK signaling is investigated in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. These cells do not express ALK and IRS family members, and do not respond to exogenously added PTN or MK. We show that expression of ALK plus IRS-1 renders these cells independent of IL-3 owing to the activation of ALK by endogenous MK. Mutational analysis reveals that this transformed phenotype of 32D cells requires kinase-active ALK as well as the interaction of ALK with IRS-1. Furthermore, 32D/ IRS-1/ALK cells display an enhanced activation of mitogen-activated protein kinase and PI3-kinase pathways, and a selective transcriptional activation of nuclear factor (NF)-jB. Small interfering RNA-mediated knockdown of the endogenous MK or p65/NF-jB revealed that both these are rate limiting for the transformed phenotype induced by ALK plus IRS-1. We conclude that the recruitment of IRS-1 to activated ALK and the activation of NF-jB are essential for the autocrine growth and survival signaling of MK.

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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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Midkine Binds to Anaplastic Lymphoma Kinase (ALK) and Acts as a Growth Factor for Different Cell Types

Cited by 304 publications

References 62 publications

Increased trabecular bone formation in mice lacking the growth factor midkine

Increased trabecular bone formation in mice lacking the growth factor midkine

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

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

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