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Redundant roles of EGFR ligands in the ERK activation waves during collective cell migration

Lin, Shuhao 京都大学 DOI:10.14989/doctor.k23761

2022.03.23

概要

Collective cell migration in mammalian tissuesis a well-orchestrated cell movement underlying fundamental biological process. Madin-Darby Canine Kidney (MDCK) cells, which hold clear apical-basolateral polarity and clear cell junctions, are frequently used as a model of collective cell migration. The EGFR (epidermal growth factor receptor)-ERK (extracellularsignal regulated kinase) signaling cascade plays a pivotal role in the collective cell migration of various cell types including MDCK cells. During collective cell migration of MDCK cells, ERK activation propagates as multiple waves from the leader cells to the follower cells in an EGFR-dependent manner.

EGFRis 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. 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. However, there are still many questions to be answered about the roles played by the endogenous EGFR ligands, because much of the current knowledge is based on exogenous bolus application of EGFR ligands to tissue culture cells. Meanwhile, knockout mice deficient in each of the seven EGFR ligand genes are viable and fertile, suggesting functional redundancy among the EGFR ligands. Therefore, abrogation of multiple EGFR ligands is essential to clearly demonstrate the activity of the endogenous EGFR ligands.

In this research, to determine which EGFR ligand mediates the propagation of the ERK activation waves during collective cell migration of MDCK cells, by utilizing Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated proteins (CRISPR/Cas9) method, the four EGFR ligands expressed in MDCK cells, EGF, TGFα, HBEGF and EREG, were knocked out one by one or in combination with others.The propagation of ERK activation waves was markedly suppressed only when allfour EGFR ligands were knocked out. Re-expression of each EGFR ligand showed that EGF, TGFα and EREG, but not HBEGF, can restore the ERK activation waves. Nevertheless, bath application of EGFR ligands failed to induce ERK activation waves in cell lines deficient in all four EGFR ligand genes. Additionally, aiming at complete elimination of the ERK activation waves, neuregulin-1 (NRG-1), a ligand for ErbB3 and ErbB4, was the next growth factor to be knocked out. However, NRG-1 deficiency caused growth arrest in the four EGFR ligand-deficient cells. Interestingly, bolus addition of EGF into the medium was not able to cancel the growth arrest. In conclusion, these results demonstrate that there is functional redundancy of EGFR ligands in the propagation of ERK activation waves during collective cell migration of MDCK cells. MDCK cells deficient in all EGFR ligands will provide a platform to examine the physiological function of each EGFR ligand.

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