title: Integrin-Associated Focal Adhesion Kinase Protects Human Embryonic Stem Cells from Apoptosis, Detachment, and Differentiation.
abstract: Human embryonic stem cells (hESCs) can be maintained in a fully defined niche on extracellular matrix substrates, to which they attach through integrin receptors. However, the underlying integrin signaling mechanisms, and their contribution to hESC behavior, are largely unknown. Here, we show that focal adhesion kinase (FAK) transduces integrin activation and supports hESC survival, substrate adhesion, and maintenance of the undifferentiated state. After inhibiting FAK kinase activity we show that hESCs undergo cell detachment-dependent apoptosis or differentiation. We also report deactivation of FAK downstream targets, AKT and MDM2, and upregulation of p53, all key players in hESC regulatory networks. Loss of integrin activity or FAK also induces cell aggregation, revealing a role in the cell-cell interactions of hESCs. This study provides insight into the integrin signaling cascade activated in hESCs and reveals in FAK a key player in the maintenance of hESC survival and undifferentiated state.
authors: North West Embryonic Stem Cell Centre, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors: Loriana
authors: L
authors: Vitillo
authors: North West Embryonic Stem Cell Centre, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors: Melissa
authors: M
authors: Baxter
authors: North West Embryonic Stem Cell Centre, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors: Banu
authors: B
authors: Iskender
authors: Pfizer Neusentis, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
authors: Paul
authors: P
authors: Whiting
authors: North West Embryonic Stem Cell Centre, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. Electronic address: sue.kimber@manchester.ac.uk.
authors: Susan J
authors: SJ
authors: Kimber
mesh_terms: D023102:Anoikis; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002449:Cell Aggregation; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D019610:Cytoprotection; D005109:Extracellular Matrix / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases