title: FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells.
abstract: Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours.
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Macagno
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
authors.forename: Jesica
authors.initials: J
authors.lastname: Diaz Vera
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
authors.forename: Yachuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
authors.forename: Iain
authors.initials: I
authors.lastname: MacPherson
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Sandilands
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Ruth
authors.initials: R
authors.lastname: Palmer
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Margaret
authors.initials: M
authors.lastname: Frame
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
authors.forename: Marcos
authors.initials: M
authors.lastname: Vidal
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004331:Drosophila melanogaster / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D020794:Receptor Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human