title: Premature ligand-receptor interaction during biosynthesis limits the production of growth factor midkine and its receptor LDL receptor-related protein 1.
abstract: 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.
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: the Departments of Pediatrics, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takei
authors.affiliation: Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hibi
authors.affiliation: Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
authors.affiliation: the Departments of Pediatrics, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: McCormick
authors.affiliation: Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Nakao
authors.affiliation: the Division of Molecular Neurobiology, National Institute for Basic Biology, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan, and.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Noda
authors.affiliation: the Department of Health Science, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi 480-0195, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Muramatsu
authors.affiliation: From the Departments of Biochemistry and. Electronic address: kkadoma@med.nagoya-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D000078792:Midkine; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C475476:LRP1 protein, human; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010982:Platelet-Derived Growth Factor; D000078792:Midkine