title: EGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP.
abstract: MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells that promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGFα and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Altogether, our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation.
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paye
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Alice
authors.initials: A
authors.lastname: Truong
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Cassandre
authors.initials: C
authors.lastname: Yip
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cimino
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Munaut
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Foidart
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Maquoi
authors.affiliation: Department of Medical Oncology, Centre Hospitalier Universitaire (CHU), Sart Tilman, Liège, Belgium.
authors.forename: Joelle
authors.initials: J
authors.lastname: Collignon
authors.affiliation: Department of Pathology, University of Liège, Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Department of Medical Oncology, Centre Hospitalier Universitaire (CHU), Sart Tilman, Liège, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Jerusalem
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium. nesounni@ulg.ac.be agnes.noel@ulg.ac.be.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège, Belgium. nesounni@ulg.ac.be agnes.noel@ulg.ac.be.
authors.forename: Nor Eddine
authors.initials: NE
authors.lastname: Sounni
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D019556:COS Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D002522:Chlorocebus aethiops; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000378:metabolism*; D051379:Mice; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism
chemical_list: D016160:Retinoblastoma Protein; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C402225:MMP17 protein, human; D053504:Matrix Metalloproteinases, Membrane-Associated