Phosphoproteomic analysis reveals the diversity of signaling behind ErbB inhibitor-induced phenotypes

Effects of kinase inhibitors on the phosphoproteome have been rarely investigated at a whole organism level. Here we performed a phosphoproteomic analysis in embryonic zebrafish to identify the signaling pathways perturbed by the ErbB receptor tyrosine kinase inhibitors at the whole organism level. The phosphorylation of the proteins associated with the PI3K/Akt, p38 MAPK, Notch, Hippo/Yap and β-catenin signaling pathways were differentially regulated by the ErbB inhibitors. Gene set enrichment analyses indicated differential neurological and myocardial phenotypes of different ErbB inhibitors. To assess the neurological and myocardial effects, motility and ventricle growth assays were performed on zebrafish embryos treated with the ErbB and downstream signaling pathway inhibitors. The treatment with the inhibitors targeting the PI3K/Akt, p38 MAPK and Notch signaling pathways along with AG1478 and Lapatinib perturbed the motility and ventricle wall growth of zebrafish embryos. Taken together, these results indicate that inhibitors with the same primary targets can affect different signaling pathways while eliciting similar physiological phenotypes.