FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion

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Stanicka, Joanna
Rieger, Leonie
O'Shea, Sandra
Cox, Orla T.
Coleman, Michael
O'Flanagan, Ciara
Addario, Barbara
McCabe, Nuala
Kennedy, Richard
O'Connor, Rosemary
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IGF-1 receptor (IGF-1R) and integrin cooperative signaling promotes cancer cell survival, proliferation, and motility, but whether this influences cancer progression and therapy responses is largely unknown. Here we investigated the non-receptor tyrosine adhesion kinase FES-related (FER), following its identification as a potential mediator of sensitivity to IGF-1R kinase inhibition in a functional siRNA screen. We found that FER and the IGF-1R co-locate in cells and can be co-immunoprecipitated. Ectopic FER expression strongly enhanced IGF-1R expression and phosphorylation on tyrosines 950 and 1131. FER phosphorylated these sites in an IGF-1R kinase-independent manner and also enhanced IGF-1-mediated phosphorylation of SHC, and activation of either AKT or MAPK-signaling pathways in different cells. The IGF-1R, β1 Integrin, FER, and its substrate cortactin were all observed to co-locate in cell adhesion complexes, the disruption of which reduced IGF-1R expression and activity. High FER expression correlates with phosphorylation of SHC in breast cancer cell lines and with a poor prognosis in patient cohorts. FER and SHC phosphorylation and IGF-1R expression could be suppressed with a known anaplastic lymphoma kinase inhibitor (AP26113) that shows high specificity for FER kinase. Overall, we conclude that FER enhances IGF-1R expression, phosphorylation, and signaling to promote cooperative growth and adhesion signaling that may facilitate cancer progression.
Breast cancer , Cortactin phosphorylation , Carcinoma cells , IGF-1 receptor , Resistance , Protein , SRC , Metastasis , Expression , Migration
Stanicka, J., Rieger, L., O’Shea, S., Cox, O., Coleman, M., O’Flanagan, C., Addario, B., McCabe, N., Kennedy, R. and O’Connor, R. (2018) 'FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion', Oncogene, 37(23), pp. 3131-3150. doi: 10.1038/s41388-017-0113-z
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