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

Sakamoto, Kazunari; Bu, Guojun; Chen, Sen; Takei, Yoshiyuki; Hibi, Kenji; Kodera, Yasuhiro; McCormick, Lynn M.; Nakao, Akimasa; Noda, Masaharu; Muramatsu, Takashi; Kadomatsu, Kenji

doi:10.1074/jbc.m110.176479

Cited by 20 publications

(19 citation statements)

References 46 publications

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“…As a mechanism of evasion of the immune response by tumors, preceding immuno-editing, we hypothesize that tumors may over-express RAP, or other as yet identified endogenous CD91 inhibitors, to impair antigen transfer. A previous study showed a correlation between elevated RAP levels and progressive disease in colon cancer patients (36). We expect this mechanism to occur during tumor initiation because antigen burden is very low, and HSP-mediated antigen uptake prevails, and allows the tumor to be firmly established.…”

Section: Discussionmentioning

confidence: 92%

Establishment of Tumor-Associated Immunity Requires Interaction of Heat Shock Proteins with CD91

Zhou

Messmer

Binder

2014

Cancer Immunology Research

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Host antitumor adaptive immune responses are generated as a result of the body’s immunosurveillance mechanisms. How the antitumor immune response is initially primed remains unclear, given that soluble tumor antigens generally are quantitatively insufficient for cross-priming and tumors lack the classical pathogen-associated molecular patterns (PAMPs) to activate costimulation and initiate cross-priming. We explored the interaction of the tumor-derived heat-shock proteins (HSP) with their common receptor (CD91) on antigen presenting cells (APCs) as a mechanism for host-priming of T cell-mediated antitumor immunity. Using targeted genetic disruption of the interaction between HSPs and CD19, we demonstrated that specific ablation of CD91 in APCs prevented the establishment of antitumor immunity. The antitumor immunity was also inhibited when the transfer of tumor-derived HSPs to APCs was prevented using an endogenous inhibitor of CD91. Inhibition was manifested in a reduction of cross-presentation of tumor-derived antigenic peptides in the lymph nodes providing a molecular basis for the observed immunity associated with tumor development. Our findings demonstrate that early in tumor development, the HSP-CD91 pathway is critical for the establishment of antitumor immunity.

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Section: Discussionmentioning

confidence: 92%

Establishment of Tumor-Associated Immunity Requires Interaction of Heat Shock Proteins with CD91

Zhou

Messmer

Binder

2014

Cancer Immunology Research

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“…S1). Notch2 (34,35), LRP1 (36)(37)(38), PTPz (39), and integrins (a4, a6, b1; ref. 40) are candidates for midkine receptors, and they were similarly expressed in both wild-type and MYCN transgenic mice.…”

Section: Resultsmentioning

confidence: 99%

Midkine Promotes Neuroblastoma through Notch2 Signaling

Kishida

Miyakawa³

et al. 2013

Cancer Research

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Midkine is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma, the most common extracranial pediatric solid tumor. Prognosis of patients with neuroblastoma in which MYCN is amplified remains particularly poor. In this study, we used a MYCN transgenic model for neuroblastoma in which midkine is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of midkine in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound midkine suppressed the growth of neuroblastoma cells in vitro and in vivo in tumor xenografts. In precancerous lesions, midkine-deficient MYCN transgenic mice exhibited defects in activation of Notch2, a candidate midkine receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the midkine-Notch2 signaling axis in neuroblastoma tumorigenesis, which implicates new strategies to treat neuroblastoma. Cancer Res; 73(4); 1318-27. Ó2012 AACR.

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“…Matsui and coworkers found two trifluoro compounds: one (PubChem 4603792) is 2-(2,6-dimethylpiperidin-1-yl)-4-thiophen-2-yl-6-(trifluoromethy)pyrimidine, and the other has a related structure that inhibits MDK effectively without cytotoxic effects at osteoblast-like cells not at cancer cells (Matsui et al, 2010). Last report by Sakamoto and coworkers in 2011 showed that the premature ligandreceptor interaction during biosynthesis limits the production of MDK and its receptor LDL receptor-related protein 1 (LRP1) (Sakamoto et al,2011). They utilized an endoplasmic reticulum (ER)-retrieval signal and a LRP1 fragment, which strongly bound to midkine and the LRP1-specialized chaperone RAP, to construct an ER-trapper.…”

Section: Midkine Inhibitorsmentioning

confidence: 99%