Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by EphB2

Fumihiko Okumura, Akiko Joo-Okumura, Keisuke Obara, Alexander Petersen, Akihiko Nishikimi, Yoshinori Fukui, Kunio Nakatsukasa, Takumi Kamura

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


Eph receptor tyrosine kinases and their ephrin ligands are overexpressed in various human cancers, including colorectal malignancies, suggesting important roles in many aspects of cancer development and progression as well as in cellular repulsive responses. The ectodomain of EphB2 receptor is cleaved by metalloproteinases (MMPs) MMP-2/MMP-9 and released into the extracellular space after stimulation by its ligand. The remaining membraneassociated fragment is further cleaved by the presenilin-dependent γ-secretase and releases an intracellular peptide that has tyrosine kinase activity. Although the cytoplasmic fragment is degraded by the proteasome, the responsible ubiquitin ligase has not been identified. Here, we show that SOCS box-containing protein SPSB4 polyubiquitinates EphB2 cytoplasmic fragment and that SPSB4 knockdown stabilizes the cytoplasmic fragment. Importantly, SPSB4 down-regulation enhances cell repulsive responses mediated by EphB2 stimulation. Altogether, we propose that SPSB4 is a previously unidentified ubiquitin ligase regulating EphB2-dependent cell repulsive responses.

Original languageEnglish
Pages (from-to)3532-3541
Number of pages10
JournalMolecular biology of the cell
Issue number24
Publication statusPublished - Nov 15 2017

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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