TY - JOUR
T1 - Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia
AU - Díaz, Begoña
AU - Yuen, Angela
AU - Iizuka, Shinji
AU - Higashiyama, Shigeki
AU - Courtneidge, Sara A.
PY - 2013/4/15
Y1 - 2013/4/15
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.201209151
DO - 10.1083/jcb.201209151
M3 - Article
C2 - 23589494
AN - SCOPUS:84876705197
SN - 0021-9525
VL - 201
SP - 279
EP - 292
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 2
ER -