The Src family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B

Hong Zhang, Fanying Meng, Ching Liang Chu, Toshiyuki Takai, Clifford A. Lowell

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)

Abstract

In classical descriptions of leukocyte chemokine signaling, Src family kinases are thought to function in a positive fashion by coupling receptor associated Gα subunits to downstream mitogen activated protein (MAP) kinase activation. However, neutrophils derived from hck-/-fgr -/- mice and dendritic cells (DCs) from fgr-/- animals manifested significantly higher intracellular signaling (Ca2+ flux, MAP kinase activation, actin polymerization) and functional responses (chemotaxis in vitro and migration in vivo) to a number of different chemokines. These kinases may mediate their effect through the inhibitory receptor PIR-B since neutrophils and DCs from pir-b-/- mice were also hyperresponsive to chemokine stimulation. In wild-type (wt) cells dephosphorylation of PIR-B was associated with maximal chemokine signaling, whereas in hck-/-fgr-/- cells PIR-B was unphosphorylated. These data support a model in which the Src family kinases Hck and Fgr function as negative regulators of myeloid cell chemokine signaling by maintaining the tonic phosphorylation of PIR-B.

Original languageEnglish
Pages (from-to)235-246
Number of pages12
JournalImmunity
Volume22
Issue number2
DOIs
Publication statusPublished - 2005 Feb

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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