Characterization of a human Rhomboid homolog, p100hRho/RHBDF1, which interacts with TGF-α family ligands

Authors

  • Takatoshi Nakagawa,

    1. Departments of Cell and Tissue Biology, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California
    Current affiliation:
    1. Department of Glycotherapeutics, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita-shi, Osaka 565-0082, Japan
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  • Annabel Guichard,

    1. Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California
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  • Carolina Perez Castro,

    1. Departments of Cell and Tissue Biology, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California
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  • Yang Xiao,

    1. Departments of Cell and Tissue Biology, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California
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  • Michael Rizen,

    1. Departments of Cell and Tissue Biology, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California
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  • Hong-Zhong Zhang,

    1. Departments of Cell and Tissue Biology, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California
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  • Diane Hu,

    1. Department of Orthopedic Surgery, University of California at San Francisco, San Francisco, California
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  • Anne Bang,

    1. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California
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  • Jill Helms,

    1. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California
    Current affiliation:
    1. Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University Medical School, Stanford, California
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  • Ethan Bier,

    1. Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California
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  • Rik Derynck

    Corresponding author
    1. Departments of Cell and Tissue Biology, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California
    • Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA 94143-0512
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Abstract

The activity of the TGF-α-like ligand Spitz in Drosophila depends on Rhomboid, a seven-transmembrane spanning protein that resides in the Golgi and acts as a serine protease to cleave Spitz, thereby releasing the soluble ligand. Several rhomboids in Drosophila have been implicated in the processing of TGF-α-like ligands, and consequent EGF receptor activation. The larger number of TGF-α-like ligands in vertebrates raises the possibility that they too might be subject to regulation by rhomboid-like proteins. We present the cDNA cloning and polypeptide sequence of an atypically long human rhomboid, which, based on the absence of critical residues for serine protease activity, is not predicted to act as a serine protease. We examined its tissue distribution, in comparison with TGF-α and the TGF-α-related protein HB-EGF, and the EGF/TGF-α receptor, in mouse embryo. This rhomboid, named p100hRho or RHBDF1, is a seven-transmembrane protein with a long N-terminal cytoplasmic extension that comprises half of the polypeptide sequence, and is found in the endoplasmic reticulum and Golgi, but not on the cell surface. It is expressed as two forms with different lengths, forms dimers and interacts with TGF-α ligands through a luminal interaction with the EGF core ectodomain. Finally, we evaluated the function of p100hRho/RHBDF1 in Drosophila, demonstrating that the short, but not the full-length form has functional activity. The characterization of this protein extends our understanding of the rhomboid family of regulatory proteins. Developmental Dynamics 233:1315–1331, 2005. © 2005 Wiley-Liss, Inc.

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