Premature ligand-receptor interaction during biosynthesis limits the production of growth factor midkine and its receptor LDL receptor-related protein 1

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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8405-8413
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number10
DOIs
StatePublished - Mar 11 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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