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2018 ; 131
(13
): ä Nephropedia Template TP
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Sequential binding of ezrin and moesin to L-selectin regulates monocyte
protrusive behaviour during transendothelial migration
#MMPMID29777033
Rey-Gallardo A
; Tomlins H
; Joachim J
; Rahman I
; Kitscha P
; Frudd K
; Parsons M
; Ivetic A
J Cell Sci
2018[Jul]; 131
(13
): ä PMID29777033
show ga
Leukocyte transendothelial migration (TEM) is absolutely fundamental to the
inflammatory response, and involves initial pseudopod protrusion and subsequent
polarised migration across inflamed endothelium. Ezrin/radixin/moesin (ERM)
proteins are expressed in leukocytes and mediate cell shape changes and polarity.
The spatio-temporal organisation of ERM proteins with their targets, and their
individual contribution to protrusion during TEM, has never been explored. Here,
we show that blocking binding of moesin to phosphatidylinositol 4,5-bisphosphate
(PIP(2)) reduces its C-terminal phosphorylation during monocyte TEM, and that
on-off cycling of ERM activity is essential for pseudopod protrusion into the
subendothelial space. Reactivation of ERM proteins within transmigrated
pseudopods re-establishes their binding to targets, such as L-selectin. Knockdown
of ezrin, but not moesin, severely impaired the recruitment of monocytes to
activated endothelial monolayers under flow, suggesting that this protein plays a
unique role in the early recruitment process. Ezrin binds preferentially to
L-selectin in resting cells and during early TEM. The moesin-L-selectin
interaction increases within transmigrated pseudopods as TEM proceeds,
facilitating localised L-selectin ectodomain shedding. In contrast, a
non-cleavable L-selectin mutant binds selectively to ezrin, driving
multi-pseudopodial extensions. Taken together, these results show that ezrin and
moesin play mutually exclusive roles in modulating L-selectin signalling and
shedding to control protrusion dynamics and polarity during monocyte TEM.