Dynamic regulation of Src-family kinases by CD45 in B cells.
CD45 is a key protein tyrosine phosphatase regulating Src-family protein tyrosine kinases (Src-PTKs) in lymphocytes; precisely how it exerts its effect remains controversial, however. We previously demonstrated that CD45 negatively regulates Lyn in the WEHI-231 B-cell line. Here we show that negative regulation by CD45 is physiologically significant in B cells and that some CD45 is constitutively associated with glycolipid-enriched microdomains (GEMs), where it inhibits Src-PTKs by dephosphorylating both the negative and the positive regulatory sites. Upon B-cell receptor (BCR) ligation, however, CD45 dissociates from GEMs within 30 seconds, inducing phosphorylation of 2 regulatory sites and activation of Src-PTKs, but subsequently reassociates with the GEMs within 15 minutes. Disruption of GEMs with methyl-beta-cyclodextrin results in abrogation of BCR-induced apoptosis in WEHI-231 cells, suggesting GEMs are critical to signals leading to the fate determination. We propose that the primary function of CD45 is inhibition of Src-PTKs and that the level of Src-PTK activation and the B-cell fate are determined in part by dynamic behavior of CD45 with respect to GEMs.
Shrivastava
Punya
P
Department of Immunology and Signal Transduction, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan.
Katagiri
Tatsuo
T
Ogimoto
Mami
M
Mizuno
Kazuya
K
Yakura
Hidetaka
H
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D002460:Cell Line; D017493:Leukocyte Common Antigens / Q000235:genetics* / Q000378:metabolism*; D021962:Membrane Microdomains; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D019061:src-Family Kinases / Q000378:metabolism*
D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens