Abstract
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.
Highlights
Collective cell migration in mammalian tissues is a well-orchestrated cell movement underlying fundamental biological processes (Friedl & Gilmour, 2009; Mayor & Etienne-Manneville, 2016)
The epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinase (ERK) signaling cascade plays a pivotal role in the collective cell migration of various cell types including MDCK cells (Yarden & Sliwkowski, 2001; Friedl & Gilmour, 2009)
We developed a new ERK biosensor named EKARrEV by replacing the substrate peptide derived from Cdc25C with that from ribosomal protein S6 kinase A1 (RSK1) (Fig 1A)
Summary
Collective cell migration in mammalian tissues is a well-orchestrated cell movement underlying fundamental biological processes (Friedl & Gilmour, 2009; Mayor & Etienne-Manneville, 2016). The epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinase (ERK) signaling cascade plays a pivotal role in the collective cell migration of various cell types including MDCK cells (Yarden & Sliwkowski, 2001; Friedl & Gilmour, 2009). EGFR is bound to and activated by a family of ligands that include epidermal growth factor (EGF), transforming growth factor alpha (TGFα), heparin-binding EGF-like growth factor (HBEGF), amphiregulin, betacellulin, epiregulin (EREG), and epigen (Harris et al, 2003). Extensive research has clarified the difference among the EGFR ligands with respect to binding affinity to four ErbB-family receptors including EGFR/ErbB1, sensitivity to proteases, subcellular localization, bioactivity to promote cell growth, and migration (Wilson et al, 2009; Singh et al, 2016). Abrogation of multiple EGFR ligands is essential to clearly demonstrate the activity of the endogenous EGFR ligands
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
