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.
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We would like to acknowledge Dr. Janina Berghoff for assistance with site-directed mutagenesis and Dr. Fionola Fogarty for assistance with the original siRNA screen. We also thank colleagues in the Cell Biology Laboratory and the Center for Cell Biology and Cancer Research for helpful discussions.
This work was funded by a Science Foundation Ireland Principal Investigator award 11/PI/1139, and the European Union FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP) Program 251480 BiomarkerIGF.
JS, LR, OTC, SO'S, MC, CO'F, BA contributed to conception and design of experiments, acquisition and interpretation of data, and drafting the manuscript. NMcC and RK contributed to conception of study and reviewing the manuscript. RO’C contributed to conception design, interpretation of data and drafting the article.
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The authors declare that they have no conflict of interest.
Sandra O’Shea and Orla Cox Joint authorship.
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Stanicka, J., Rieger, L., O’Shea, S. et al. FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion. Oncogene 37, 3131–3150 (2018). https://doi.org/10.1038/s41388-017-0113-z