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Development of T‐leukaemias in CD45 tyrosine phosphatase‐deficient mutant lck mice
Author(s) -
Baker Matthew,
Gamble John,
Tooze Reuben,
Higgins Dominic,
Yang Feng Tang,
O'Brien Patricia C.M.,
Coleman Nicholas,
Pingel Sabine,
Turner Martin,
Alexander Denis R.
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.17.4644
Subject(s) - biology , autophosphorylation , protein tyrosine phosphatase , proto oncogene tyrosine protein kinase src , tyrosine kinase , receptor tyrosine kinase , cancer research , dephosphorylation , tyrosine phosphorylation , ror1 , tyrosine , t cell receptor , phosphorylation , microbiology and biotechnology , t cell , phosphatase , signal transduction , platelet derived growth factor receptor , immunology , biochemistry , receptor , protein kinase a , immune system , growth factor
The CD45 tyrosine phosphatase lowers T‐cell antigen receptor signalling thresholds by its positive actions on p56 lck tyrosine kinase function. We now show that mice expressing active lck F505 at non‐oncogenic levels develop aggressive thymic lymphomas on a CD45 −/− background. CD45 suppresses the tumorigenic potential of the kinase by dephosphorylation of the Tyr394 autophosphorylation site. In CD45 −/− thymocytes the kinase is switched to a hyperactive oncogenic state, resulting in increased resistance to apoptosis. Transformation occurs in early CD4 − CD8 − thymocytes during the process of TCR‐β chain rearrangement by a recombinase‐independent mechanism. Our findings represent the first example in which a tyrosine phosphatase in situ prevents the oncogenic actions of a Src family tyrosine kinase.