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Direct binding of the human homologue of the Drosophila disc large tumor suppressor gene to seven-pass transmembrane proteins, tumor endothelial marker 5 (TEM5), and a novel TEM5-like protein

Oncogene volume 23, pages 3889–3897 (2004)Cite this article

Abstract

The human homologue of the Drosophila discs large tumor suppressor gene (hDlg) is a member of the membrane-associated guanylate kinase family with three PSD-95/Dlg/ZO-1 (PDZ) domains. hDlg has been shown to bind tumor suppressor proteins, adenomatous polyposis coli (APC) and protein tyrosine phosphatase and tensin homologue (PTEN), and several viral oncoproteins, and has been implicated in the negative regulation of cell proliferation. hDlg has furthermore been shown to localize at the plasma membrane of synapses and to scaffold cell surface receptors and channels. In epithelial cells, hDlg localizes at the basolateral plasma membrane, but its localization mechanism is unknown. We searched here for a transmembrane protein that directly bound to hDlg. hDlg bound tumor endothelial marker 5 (TEM5), a seven-pass transmembrane protein that is homologous to the family B of G-protein-coupled receptors (GPCRs). TEM5 has previously been reported to display elevated expression during tumor angiogenesis and neoangiogenesis. The PDZ domains of hDlg bound the C-terminal PDZ-binding motif of TEM5. The expression of TEM5 was detected in endothelial cells of embryonic liver, where hDlg colocalized with TEM5. hDlg furthermore bound a novel seven-pass transmembrane protein, which was homologous to TEM5, and was named here a TEM5-like protein (TEM5-like). These results suggest that hDlg localizes at the plasma membrane through TEM5 and TEM5-like and furthermore scaffolds these GPCRs in endothelial cells during tumor angiogenesis and neoangiogenesis.

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Abbreviations

aa:

amino acid(s)

Ab:

antibody

EGFP:

enhanced green fluorescent protein

GK:

guanylate kinase-like

GPCR:

G-protein-coupled receptor

GPS:

GPCR proteolysis site

GST:

glutathione S-transferase

hDlg:

human homologue of the Drosophila discs large tumor suppressor

LRR:

leucine-rich repeat

MAGUK:

membrane-associated guanylate kinase homologue

MBP:

maltose-binding protein

PDZ:

PSD-95/Dlg/ZO-1

RTQ-RT-PCR:

real-time quantitative reverse transcriptase/polymerase chain reaction

SDS–PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

SH3:

Src homology-3

TEM5:

tumor endothelial marker 5

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Acknowledgements

We thank Dr T Akiyama (The University of Tokyo, Tokyo, Japan) for providing us with the cDNA of hDlg, and Dr S Nishikawa (Kyoto University, Kyoto, Japan), Dr M Shibuya (The University of Tokyo, Tokyo, Japan), and Dr Y Sato (Tohoku University, Miyagi, Japan) for helpful discussion. The investigation was supported by grants-in-aid for Scientific Research and for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (2002, 2003); and by the Kanae Foundation for Life & Socio-Medical Science (to KI).

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Author notes

  1. Yasunori Yamamoto

    Present address: Division of Molecular Neurobiology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji-cho, Okazaki, 444-8585, Japan

  2. Masanori Asada

    Present address: Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

  3. Akihisa Mino

    Present address: Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA

  4. Kenji Mandai

    Present address: Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD, 21205-2185, USA

Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, 565-0871, Japan

    Yasunori Yamamoto, Kenji Irie, Masanori Asada, Akihisa Mino, Kenji Mandai & Yoshimi Takai

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Correspondence to Yoshimi Takai.

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Yamamoto, Y., Irie, K., Asada, M. et al. Direct binding of the human homologue of the Drosophila disc large tumor suppressor gene to seven-pass transmembrane proteins, tumor endothelial marker 5 (TEM5), and a novel TEM5-like protein. Oncogene 23, 3889–3897 (2004). https://doi.org/10.1038/sj.onc.1207495

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