TY - JOUR
T1 - The Src family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B
AU - Zhang, Hong
AU - Meng, Fanying
AU - Chu, Ching Liang
AU - Takai, Toshiyuki
AU - Lowell, Clifford A.
N1 - Funding Information:
We thank Yongmei Hu, Hong Yu, Attila Mócsai, Clare Abram, Jessica Van Ziffle, and members of the Eric Brown, Art Weiss, and Tony DeFranco groups who provided thoughtful discussions and critiques throughout this project. We acknowledge Dr. Hiromi Kubagawa for gifts of anti-PIR-B mAb and polyclonal Abs. We also thank Drs. Michelle Hermiston, Hua Chen, Neetu Gupta, Kenji Kabashima, Mehardad Matloubian, and Scott Simon for experimental help. This work was supported by National Institutes of Health grant DK58066 to C.A.L. and by the CREST Program of Japan Science and Technology Corporation. C.A.L. is a Scholar of the Leukemia and Lymphoma Society.
PY - 2005/2
Y1 - 2005/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=13844276957&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13844276957&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2005.01.004
DO - 10.1016/j.immuni.2005.01.004
M3 - Article
C2 - 15723811
AN - SCOPUS:13844276957
SN - 1074-7613
VL - 22
SP - 235
EP - 246
JO - Immunity
JF - Immunity
IS - 2
ER -
