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Serine Phosphorylation of L-Selectin Regulates ERM Binding, Clustering, and Monocyte Protrusion in Transendothelial Migration.
- Source :
-
Frontiers in immunology [Front Immunol] 2019 Sep 25; Vol. 10, pp. 2227. Date of Electronic Publication: 2019 Sep 25 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- The migration of circulating leukocytes toward damaged tissue is absolutely fundamental to the inflammatory response, and transendothelial migration (TEM) describes the first cellular barrier that is breached in this process. Human CD14 <superscript>+</superscript> inflammatory monocytes express L-selectin, bestowing a non-canonical role in invasion during TEM. In vivo evidence supports a role for L-selectin in regulating TEM and chemotaxis, but the intracellular mechanism is poorly understood. The ezrin-radixin-moesin (ERM) proteins anchor transmembrane proteins to the cortical actin-based cytoskeleton and additionally act as signaling adaptors. During TEM, the L-selectin tail within transmigrating pseudopods interacts first with ezrin to transduce signals for protrusion, followed by moesin to drive ectodomain shedding of L-selectin to limit protrusion. Collectively, interaction of L-selectin with ezrin and moesin fine-tunes monocyte protrusive behavior in TEM. Using FLIM/FRET approaches, we show that ERM binding is absolutely required for outside-in L-selectin clustering. The cytoplasmic tail of human L-selectin contains two serine (S) residues at positions 364 and 367, and here we show that they play divergent roles in regulating ERM binding. Phospho-S364 blocks direct interaction with ERM, whereas molecular modeling suggests phospho-S367 likely drives desorption of the L-selectin tail from the inner leaflet of the plasma membrane to potentiate ERM binding. Serine-to-alanine mutagenesis of S367, but not S364, significantly reduced monocyte protrusive behavior in TEM under flow conditions. Our data propose a model whereby L-selectin tail desorption from the inner leaflet of the plasma membrane and ERM binding are two separable steps that collectively regulate protrusive behavior in TEM.<br /> (Copyright © 2019 Newe, Rzeniewicz, König, Schroer, Joachim, Rey-Gallardo, Marrink, Deka, Parsons and Ivetic.)
- Subjects :
- Cell Membrane metabolism
Cells, Cultured
Cluster Analysis
Cytoplasm metabolism
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Humans
Leukocytes metabolism
Monocytes metabolism
Signal Transduction physiology
THP-1 Cells
Cytoskeletal Proteins metabolism
L-Selectin metabolism
Membrane Proteins metabolism
Microfilament Proteins metabolism
Phosphorylation physiology
Serine metabolism
Transendothelial and Transepithelial Migration physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 10
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 31608057
- Full Text :
- https://doi.org/10.3389/fimmu.2019.02227