Syk-mediated translocation of PI3Kδ to the leading edge controls lamellipodium formation and migration of leukocytes

The non-receptor tyrosine kinase Syk is mainly expressed in the
hematopoietic system and plays an essential role in β2
integrin-mediated leukocyte activation. To elucidate the signaling
pathway downstream of Syk during β2 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 I(A). Syk-Tyr323 was
found to be critical for the enrichment of the catalytic subunit
p110delta of PI3K class I(A) 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 p110δ 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 β2 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 p110δ signaling for β2
integrin-mediated migration which is a prerequisite for efficient
PMN recruitment in vivo.