Dynamic regulation of Src-family tyrosine kinases by CD45

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Initiation of immune responses is determined by activation of Src-family protein tyrosine kinases (Src-PTKs) upon antigen receptor ligation. Activity of Src-PTKs is regulated, among others, by tyrosine phosphorylation of two tyrosine residues: the autophosphorylation and COOH-terminal negative regulatory sites. CD45, the prototypic receptor-type protein tyrosine phosphatase, has been shown to be a major regulator of Src-PTKs. The precise way in which CD45 exerts its effect is still controversial, however. Our earlier studies showed that CD45 inhibits Lyn activity in a B cell line by dephosphorylating both the autopfibsphorylation and negative regulatory tyrosine residues, and that B cell receptor (BCR) ligation induces phosphorylation of both regulatory sites, suggesting CD45 action on Lyn is diminished upon BCR ligation. In this presentation, we report that in contrast to most studies reported thus far, negative regulation by CD45 is generally operative in B cells, and that some CD45 is constitutively associated with glycolipid-enriched microdomains (GEMs), where it inhibits Src-PTK activity. Upon BCR ligation, however, CD45 dissociates from GEMs within 1 min, leading to activation of Src-PTKs, and then subsequently re-associates with the GEMs within 60 min. CD45 is not involved in the regulation of movement of IgM, Src-PTKs and Csk with respect to GEMs. We propose that the primary role of GEM-associated CD45 is inhibition of Src-PTKs, and that its dynamic behavior of CD45 determines the level of Src-PTK activation and the cell fate.