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

Area of Science:

• Molecular Biology
• Developmental Biology
• Pharmacology

Background:

• Kinase inhibitors are crucial in targeted therapies, but their impact on the whole-organism phosphoproteome is understudied.
• ErbB receptor tyrosine-protein kinase inhibitors are widely used, yet their systemic effects require further investigation.

Purpose of the Study:

• To investigate the impact of ErbB inhibitors (gefitinib, lapatinib, AG1478) on the phosphoproteome at the whole-organism level using embryonic zebrafish.
• To identify signaling pathways perturbed by these inhibitors and assess their effects on neurological and myocardial development.

Main Methods:

• Phosphoproteomic analysis was conducted on embryonic zebrafish treated with ErbB inhibitors.
• Gene set enrichment analysis was used to identify affected signaling pathways.
• Motility and ventricle growth assays were performed to evaluate neurological and myocardial phenotypes.

Main Results:

• ErbB inhibitors differentially regulated protein phosphorylation in key signaling pathways including PI3K/Akt, p38 MAPK, Notch, Hippo/Yap, and β-catenin.
• Inhibitors targeting PI3K/Akt, p38 MAPK, and Notch pathways, along with AG1478 and lapatinib, affected zebrafish embryo motility and ventricle growth.
• Distinct neurological and myocardial phenotypes were observed for different ErbB inhibitors.

Conclusions:

• ErbB inhibitors can modulate diverse signaling pathways beyond their primary targets.
• Overlapping primary targets do not guarantee identical downstream pathway effects or physiological outcomes.
• This study highlights the complexity of kinase inhibitor action at the organismal level and their potential for varied developmental effects.