Epidermal growth factor receptor (EGFR) plays a pivotal role in collective cell 
migration by mediating cell-to-cell propagation of extracellular 
signal-regulated kinase (ERK) activation. Here, we aimed to determine which EGFR 
ligands mediate the ERK activation waves. We found that epidermal growth factor 
(EGF)-deficient cells exhibited lower basal ERK activity than the cells 
deficient in heparin-binding EGF (HBEGF), transforming growth factor alpha 
(TGFα) or epiregulin (EREG), but all cell lines deficient in a single EGFR 
ligand retained the ERK activation waves. Surprisingly, ERK activation waves 
were markedly suppressed, albeit incompletely, only when all four EGFR ligands 
were knocked out. Re-expression of the EGFR ligands revealed that all but HBEGF 
could restore the ERK activation waves. Aiming at complete elimination of the 
ERK activation waves, we further attempted to knockout NRG1, a ligand for ErbB3 
and ErbB4, and found that NRG1-deficiency induced growth arrest in the absence 
of all four EGFR ligand genes. Collectively, these results showed that EGFR 
ligands exhibit remarkable redundancy in the propagation of ERK activation waves 
during collective cell migration.