%0 Journal Article
%T Syk-Mediated Translocation of PI3K¦Ä to the Leading Edge Controls Lamellipodium Formation and Migration of Leukocytes
%A J¨¹rgen Schymeinsky
%A Cornelia Then
%A Anca Sindrilaru
%A Ronald Gerstl
%A Zolt¨¢n Jakus
%A Victor L. J. Tybulewicz
%A Karin Scharffetter-Kochanek
%A Barbara Walzog
%J PLOS ONE
%D 2007
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0001132
%X The non-receptor tyrosine kinase Syk is mainly expressed in the hematopoietic system and plays an essential role in ¦Â2 integrin-mediated leukocyte activation. To elucidate the signaling pathway downstream of Syk during ¦Â2 integrin (CD11/CD18)-mediated migration and extravasation of polymorphonuclear neutrophils (PMN), we generated neutrophil-like differentiated HL-60 (dHL-60) cells expressing a fluorescently tagged Syk mutant lacking the tyrosine residue at the position 323 (Syk-Tyr323) that is known to be required for the binding of the regulatory subunit p85 of the phosphatidylinositol 3-kinase (PI3K) class IA. Syk-Tyr323 was found to be critical for the enrichment of the catalytic subunit p110¦Ä of PI3K class IA as well as for the generation of PI3K products at the leading edge of the majority of polarized cells. In accordance, the translocation of PI3K p110¦Ä to the leading edge was diminished in Syk deficient murine PMN. Moreover, the expression of EGFP-Syk Y323F interfered with proper cell polarization and it impaired efficient migration of dHL-60 cells. In agreement with a major role of ¦Â2 integrins in the recruitment of phagocytic cells to sites of lesion, mice with a Syk-deficient hematopoietic system demonstrated impaired PMN infiltration into the wounded tissue that was associated with prolonged cutaneous wound healing. These data imply a novel role of Syk via PI3K p110¦Ä signaling for ¦Â2 integrin-mediated migration which is a prerequisite for efficient PMN recruitment in vivo.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001132