FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Drosophila melanogaster Epithelia and Human Cancer Cells

Autor: Iain R. Macpherson, Juan Pablo Macagno, Marcos Vidal, Yachuan Yu, Margaret C. Frame, Ruth H. Palmer, Emma Sandilands, Jim C. Norman, Jesica Diaz Vera
Rok vydání: 2014
Předmět:
MAPK/ERK pathway
Receptor recycling
Cancer Research
Arthropoda
lcsh:QH426-470
MAP Kinase Signaling System
Receptor Protein-Tyrosine Kinases
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology)
Molecular Biology
Microbiology
Biochemistry or Biopharmacy)
Breast Neoplasms
Research and Analysis Methods
Cell Fate Determination
Receptor tyrosine kinase
Focal adhesion
QH301
Model Organisms
Cell Line
Tumor
Cancer Genetics
Genetics
Animals
Humans
Phosphorylation
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi)
molekylärbiologi
mikrobiologi
biokemi eller biofarmaci)
Molecular Biology
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
Cell Proliferation
PTK2B
biology
Kinase
Drosophila Melanogaster
Biochemistry and Molecular Biology
Organisms
Biology and Life Sciences
Epithelial Cells
Animal Models
Invertebrates
Cell biology
Insects
lcsh:Genetics
Focal Adhesion Kinase 1
Mitogen-activated protein kinase
Genetics of Disease
biology.protein
Female
Drosophila
Biokemi och molekylärbiologi
Research Article
Developmental Biology
Zdroj: PLoS Genetics, Vol 10, Iss 3, p e1004262 (2014)
PLoS Genetics
Macagno, J P, Diaz Vera, J, Yu, Y, Macpherson, I, Sandilands, E, Palmer, R, Norman, J C, Frame, M & Vidal, M 2014, ' FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Drosophila melanogaster Epithelia and Human Cancer Cells ', PLoS Genetics, vol. 10, no. 3, e1004262 . https://doi.org/10.1371/journal.pgen.1004262
ISSN: 1553-7404
DOI: 10.1371/journal.pgen.1004262
Popis: 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.
Author Summary Due to their deregulation in cancer and their potential to be inhibited by small chemical compounds, tyrosine kinases are among the most important targets under consideration for cancer therapeutics. One such oncogenic tyrosine kinase is FAK, which is known to regulate cellular signalling downstream of Integrins and Receptor Tyrosine Kinases (RTK) at the cell surface. In this study, however, we report that FAK can act as a suppressor of oncogenic Receptor Tyrosine Kinases. This mechanism was observed in fruit fly tissues in vivo and human cancer-derived cells in vitro, which additionally suggests it is an evolutionary conserved mechanism in humans. FAK mediated this inhibition by controlling the sub-cellular localisation of receptors, via suppression of receptor recycling to the cell surface. These results suggest that in some particular cancer contexts such as RTK-driven tumours, FAK may act as a tumour suppressor and therefore, may not be a valid drug target.
Databáze: OpenAIRE
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