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

Begoña Díaz, Angela Yuen, Shinji Iizuka, Shigeki Higashiyama, Sara Courtneidge

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)279-292
Number of pages14
JournalJournal of Cell Biology
Volume201
Issue number2
DOIs
StatePublished - Apr 15 2013
Externally publishedYes

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Epidermal Growth Factor
Epidermal Growth Factor Receptor
Neoplasms
Paracrine Communication
Cell Hypoxia
Metalloproteases
Cellular Structures
Cell Communication
Heparin
Podosomes
Hypoxia
Intercellular Signaling Peptides and Proteins
Ligands

ASJC Scopus subject areas

  • Cell Biology

Cite this

Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. / Díaz, Begoña; Yuen, Angela; Iizuka, Shinji; Higashiyama, Shigeki; Courtneidge, Sara.

In: Journal of Cell Biology, Vol. 201, No. 2, 15.04.2013, p. 279-292.

Research output: Contribution to journalArticle

Díaz, Begoña ; Yuen, Angela ; Iizuka, Shinji ; Higashiyama, Shigeki ; Courtneidge, Sara. / Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. In: Journal of Cell Biology. 2013 ; Vol. 201, No. 2. pp. 279-292.
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