MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes.
MRP14 (S100A9) is the major calcium-binding protein of neutrophils and monocytes. Targeted gene disruption reveals an essential role of this S100 protein for transendothelial migration of phagocytes. The underlying molecular mechanism comprises major alterations of cytoskeletal metabolism. MRP14, in complex with its binding partner MRP8 (S100A8), promotes polymerization of microtubules. MRP14 is specifically phosphorylated by p38 mitogen-activated protein kinase (MAPK). This phosphorylation inhibits MRP8/MRP14-induced tubulin polymerization. Phosphorylation of MRP14 is antagonistically regulated by binding of MRP8 and calcium. The biologic relevance of these findings is confirmed by the fact that MAPK p38 fails to stimulate migration of MRP14(-/-) granulocytes in vitro and MRP14(-/-) mice show a diminished recruitment of granulocytes into the granulation tissue during wound healing in vivo. MRP14(-/-) granulocytes contain significantly less polymerized tubulin, which subsequently results in minor activation of Rac1 and Cdc42 after stimulation of p38 MAPK. Thus, the complex of MRP8/MRP14 is the first characterized molecular target integrating MAPK- and calcium-dependent signals during migration of phagocytes.
Institute of Experimental Dermatology, Department of Pediatrics, University of Münster, Röntgenstrasse 21, D-48149 Münster, Germany.
Thomas
T
Vogl
Stephan
S
Ludwig
Matthias
M
Goebeler
Anke
A
Strey
Irmgard S
IS
Thorey
Rudolf
R
Reichelt
Dirk
D
Foell
Volker
V
Gerke
Marie P
MP
Manitz
Wolfgang
W
Nacken
Sabine
S
Werner
Clemens
C
Sorg
Johannes
J
Roth
D000818:Animals; D040501:Calgranulin A / Q000502:physiology*; D040502:Calgranulin B / Q000235:genetics / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000502:physiology*; D006098:Granulocytes / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000502:physiology* / Q000648:ultrastructure; D010586:Phagocytes / Q000502:physiology* / Q000648:ultrastructure
D040501:Calgranulin A; D040502:Calgranulin B