title: Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia.
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.
authors.affiliation: Cancer Center, Tumor Microenvironment Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. bdiaz@sanfordburnham.org
authors.forename: Begoña
authors.initials: B
authors.lastname: Díaz
authors.forename: Angela
authors.initials: A
authors.lastname: Yuen
authors.forename: Shinji
authors.initials: S
authors.lastname: Iizuka
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.forename: Sara A
authors.initials: SA
authors.lastname: Courtneidge
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072199:ADAM12 Protein; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C587883:HBEGF protein, human; C497442:HIF1A protein, human; D066257:Heparin-binding EGF-like Growth Factor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human