The Src family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B.
In classical descriptions of leukocyte chemokine signaling, Src family kinases are thought to function in a positive fashion by coupling receptor associated Galpha 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.
Zhang
Hong
H
Department of Laboratory Medicine , University of California, San Francisco , San Francisco, California 94143, USA.
Meng
Fanying
F
Chu
Ching-Liang
CL
Takai
Toshiyuki
T
Lowell
Clifford A
CA
D000818:Animals; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases
D018925:Chemokines; D047908:Intracellular Signaling Peptides and Proteins; D019402:Macrophage Inflammatory Proteins; C105949:Pirb protein, mouse; D011518:Proto-Oncogene Proteins; D011971:Receptors, Immunologic; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse