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Quantitative Measurement of Invadopodia-mediated Extracellular Matrix Proteolysis in Single and Multicellular Contexts
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Deletion of the plexin-D1 ectodomain leads to anoikis by suppressing integrin inside-out signaling

Toshihiko Toyofuku1, Takako Ishikawa1, Atsushi Kumanogoh2,3,4

  • 1Department of Immunology and Molecular Medicine, Graduate School of Medicine, The Center of Medical Innovation and Translational Research, Osaka University, Suita, Osaka 565-0871, Japan.

Molecular Biology of the Cell
|April 23, 2025
PubMed

Insights

Plexin-D1 cleavage in cancer cells yields fragments that either induce anoikis by blocking integrin signaling or promote branching tubule formation by activating Met receptor tyrosine kinase signaling, thus determining cancer cell fate.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Plexin-D1 is expressed in endothelial and cancer cells, influencing cell growth, migration, and proliferation.
  • Proteinase cleavage of plexin-D1 occurs on cancer cells, generating fragments with potentially distinct functions.

Purpose of the Study:

  • To investigate the role of cleaved plexin-D1 fragments in cellular behavior.
  • To elucidate the mechanisms by which plexin-D1 influences cell adhesion, survival, and morphogenesis.

Main Methods:

  • Madin-Darby canine kidney (MDCK) cells overexpressing truncated plexin-D1 variants (lacking ectodomain or cytoplasmic domain) were cultured in Matrigel.
  • Adhesion assays were performed to assess extracellular matrix (ECM) interactions.
  • The role of the hepatocyte growth factor receptor (Met) was examined using loss-of-function and inhibitor studies.

Main Results:

  • MDCK cells expressing plexin-D1 lacking the ectodomain (plexin-D1 ΔEC) underwent apoptosis and lost ECM affinity, suggesting anoikis induction via blocked integrin signaling.
  • MDCK cells expressing full-length plexin-D1 or plexin-D1 lacking the cytoplasmic domain (plexin-D1 ΔIC) formed multicellular branching tubular structures.
  • This branching morphogenesis was dependent on Met receptor activity, indicating plexin-D1 associates with and activates Met.

Conclusions:

  • Cleaved plexin-D1 fragments have distinct roles in cancer cell fate.
  • Plexin-D1 ΔEC induces anoikis by interfering with integrin-mediated adhesion.
  • Plexin-D1 associates with Met via its extracellular domain, activating Met kinase activity and promoting branching tubule formation.

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