RRC ID |
82023
|
Author |
Deguchi E, Lin S, Hirayama D, Matsuda K, Tanave A, Sumiyama K, Tsukiji S, Otani T, Furuse M, Sorkin A, Matsuda M, Terai K.
|
Title |
Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters in collective cell migration of epithelial cells.
|
Journal |
Cell Rep
|
Abstract |
Canonical epidermal growth factor (EGF) receptor (EGFR) activation involves the binding of seven EGFR ligands (EGFRLs); however, their extracellular dynamics remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding, we show that epiregulin (EREG), a low-affinity EGFRL, rapidly and efficiently activates EGFR in Madin-Darby canine kidney (MDCK) epithelial cells and mouse epidermis. During collective cell migration, EGFR and extracellular signal-regulated kinase (ERK) activation waves propagate in an a disintegrin and metalloprotease 17 (ADAM17) sheddase- and EGFRL-dependent manner. Upon induced EGFRL shedding, low-affinity ligands EREG and amphiregulin (AREG) mediate faster and broader ERK waves than high-affinity ligands. Tight/adherens junction integrity is essential for ERK activation propagation, suggesting that tight intercellular spaces prefer the low-affinity EGFRLs for efficient signal transmission. In EREG-deficient mice, ERK wave propagation and cell migration were impaired during skin wound repair. We additionally show that heparin-binding EGF-like growth factor (HBEGF) primarily promotes surrounding cell motility. Our findings underscore the pivotal role of low-affinity EGFRLs in rapid intercellular signal transmission.
|
Volume |
43(11)
|
Pages |
114986
|
Published |
2024-11-14
|
DOI |
10.1016/j.celrep.2024.114986
|
PII |
S2211-1247(24)01337-8
|
PMID |
39546398
|
MeSH |
ADAM17 Protein / metabolism
Amphiregulin / metabolism
Animals
Cell Movement*
Dogs
Epidermis / metabolism
Epiregulin* / metabolism
Epithelial Cells* / metabolism
ErbB Receptors* / metabolism
Extracellular Signal-Regulated MAP Kinases / metabolism
Heparin-binding EGF-like Growth Factor / genetics
Heparin-binding EGF-like Growth Factor / metabolism
Humans
Ligands
Madin Darby Canine Kidney Cells
Mice
Signal Transduction
Wound Healing
|
Resource |
Human and Animal Cells |
MDCK(RCB0995) |
DNA material |
pCMV-VSV-G-RSV-Rev (RDB04393) |