The inositol polyphosphate 5-phosphatase ship is a crucial negative regulator of B cell antigen receptor signaling.
Ship is an Src homology 2 domain containing inositol polyphosphate 5-phosphatase which has been implicated as an important signaling molecule in hematopoietic cells. In B cells, Ship becomes associated with Fcgamma receptor IIB (FcgammaRIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)-FcgammaRIIB coligation. The function of Ship in lymphocytes was investigated in Ship-/- recombination-activating gene (Rag)-/- chimeric mice generated from gene-targeted Ship-/- embryonic stem cells. Ship-/-Rag-/- chimeras showed reduced numbers of B cells and an overall increase in basal serum Ig. Ship-/- splenic B cells displayed prolonged Ca2+ influx, increased proliferation in vitro, and enhanced mitogen-activated protein kinase (MAPK) activation in response to BCR-FcgammaRIIB coligation. These results demonstrate that Ship plays an essential role in FcgammaRIIB-mediated inhibition of BCR signaling, and that Ship is a crucial negative regulator of Ca2+ flux and MAPK activation.
Amgen Institute, Toronto, Ontario, Canada M5G 2C1. qliu@amgen.com
Q
Q
Liu
A J
AJ
Oliveira-Dos-Santos
S
S
Mariathasan
D
D
Bouchard
J
J
Jones
R
R
Sarao
I
I
Kozieradzki
P S
PS
Ohashi
J M
JM
Penninger
D J
DJ
Dumont
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D007136:Immunoglobulins / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
D016207:Cytokines; D018398:Homeodomain Proteins; D007136:Immunoglobulins; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; C064658:RAG-1 protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002118:Calcium