CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling

The regulation of tyrosine phosphorylation and associated signalling throug h antigen, growth-factor and cytokine receptors is mediated by the reciproc al activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPases)(1). The transmembrane PTPase CD45 is a key regulator of antigen receptor signalling in T and B cells(2,3). Src-family kinases have been ide ntified as primary molecular targets for CD45 (ref. 4). However, CD45 is hi ghly expressed in all haematopoietic lineages at all stages of development( 5), indicating that CD45 could regulate other cell types and might act on a dditional substrates. Here we show that CD45 suppresses JAK (Janus kinase) kinases and negatively regulates cytokine receptor signalling. Targeted dis ruption of the cd45 gene leads to enhanced cytokine and interferon-receptor -mediated activation of JAKs and STAT (signal transducer and activators of transcription) proteins. In vitro, CD45 directly dephosphorylates and binds to JAKs. Functionally, CD45 negatively regulates interleukin-3-mediated ce llular proliferation, erythropoietin-dependent haematopoieisis and antivira l responses in vitro and in vivo. Our data identify an unexpected and novel function for CD45 as a haematopoietic JAK phosphatase that negatively regu lates cytokine receptor signalling.