Controlled dimerization of insulin-like grown factor-1 and insulin receptors reveal shared and distinct activities of holo and hybrid receptors
Breast cancer development and progression is influenced by insulin-like growth factor 1 (IGF1R) and insulin receptor (InsR) signaling that drive cancer phenotypes such as cell growth, proliferation, and migration. IGF1R and InsR form IGF1R/InsR hybrid receptors (HybR) consisting of one molecule of IGF1R and one molecule of InsR. The specific signaling and functions of HybR are largely unknown as HybR is activated by both IGF1 and insulin, and no cellular system expresses HybR in the absence of holo-IGF1R or holo-InsR. Here we studied the role of HybR by constructing inducible chimeric receptors, and compared HybR signaling with that of holo-IGF1R and holo-InsR. We cloned chemically-inducible chimeric IGF1R and InsR constructs consisting of the extracellular domains of the p75 nerve growth factor receptor fused to the intracellular β subunit of IGF1R or InsR, and a dimerization domain. Dimerization with the drugs AP20187 or AP21967 allowed specific and independent activation of holoIGF1R, holo-InsR, or HybR, resulting in activation of the PI3K pathway. Holo-IGF1R and HybR both promoted cell proliferation and glucose uptake, whereas holo-InsR only promoted glucose uptake, and only holo-IGF1R showed antiapoptotic effects. We also found that the three receptors differentially regulated gene expression: holo-IGF1R and HybR upregulated EGR3; holo-InsR specifically downregulated JUN and BCL2L1; holo-InsR downregulated, but HybR upregulated HK2; and HybR specifically upregulated FHL2, ITGA6, and PCK2. Our findings suggest that when expressed and activated in mammary epithelial cells, HybR acts in a manner similar to IGF1R, and supports further investigation of the role of HybR in breast cancer.