title: Development of T-leukaemias in CD45 tyrosine phosphatase-deficient mutant lck mice.
abstract: 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-beta 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.
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Programme of Molecular Immunology, The Babraham Institute, Cambridge CB2 4AT, UK.
authors.forename: M
authors.initials: M
authors.lastname: Baker
authors.forename: J
authors.initials: J
authors.lastname: Gamble
authors.forename: R
authors.initials: R
authors.lastname: Tooze
authors.forename: D
authors.initials: D
authors.lastname: Higgins
authors.forename: F T
authors.initials: FT
authors.lastname: Yang
authors.forename: P C
authors.initials: PC
authors.lastname: O'Brien
authors.forename: N
authors.initials: N
authors.lastname: Coleman
authors.forename: S
authors.initials: S
authors.lastname: Pingel
authors.forename: M
authors.initials: M
authors.lastname: Turner
authors.forename: D R
authors.initials: DR
authors.lastname: Alexander
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D017931:DNA Primers; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D019426:Integrases; D015458:Leukemia, T-Cell / Q000201:enzymology* / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000502:physiology*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D045522:Recombinases; D013953:Thymus Neoplasms / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; D045522:Recombinases; D011505:Protein-Tyrosine Kinases; D004254:DNA Nucleotidyltransferases; D019426:Integrases; C115006:integron integrase IntI1; D017493:Leukocyte Common Antigens