Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia.

Notch regulates cell-cell contact-dependent signaling and is activated by hypoxia, a microenvironmental condition that promotes cellular invasion during both normal physiology and disease. The mechanisms by which hypoxia and Notch regulate cellular invasion are not fully elucidated. In this paper, we show that, in cancer cells, hypoxia increased the levels and activity of the ADAM12 metalloprotease in a Notch signaling-dependent manner, leading to increased ectodomain shedding of the epidermal growth factor (EGF) receptor (EGFR) ligand heparin-binding EGF-like growth factor. Released HB-EGF induced the formation of invadopodia, cellular structures that aid cancer cell invasion. Thus, we describe a signaling pathway that couples cell contact-dependent signaling with the paracrine activation of the EGFR, indicating cross talk between the Notch and EGFR pathways in promoting cancer cell invasion. This signaling pathway might regulate the coordinated acquisition of invasiveness by neighboring cells and mediate the communication between normoxic and hypoxic areas of tumors to facilitate cancer cell invasion.
AuthorsBegoña Díaz, Angela Yuen, Shinji Iizuka, Shigeki Higashiyama, Sara A Courtneidge
JournalThe Journal of cell biology (J Cell Biol) Vol. 201 Issue 2 Pg. 279-92 (Apr 15 2013) ISSN: 1540-8140 [Electronic] United States
PMID23589494 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • HBEGF protein, human
  • HIF1A protein, human
  • Heparin-binding EGF-like Growth Factor
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • ADAM 12 protein
  • ADAM Proteins
  • ADAM Proteins (genetics, metabolism)
  • Cell Communication (drug effects, genetics)
  • Cell Hypoxia (drug effects)
  • Cell Line, Tumor
  • Epithelial Cells (drug effects, metabolism, pathology)
  • Epithelium (drug effects, metabolism, pathology)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
  • Intercellular Signaling Peptides and Proteins (chemistry, metabolism, pharmacology)
  • Membrane Proteins (genetics, metabolism)
  • Models, Biological
  • Protein Structure, Tertiary
  • Pseudopodia (metabolism)
  • Receptors, Notch (metabolism)
  • Signal Transduction (drug effects, genetics)

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