Development of T-leukaemias in CD45 tyrosine phosphatase-deficient mutant lck mice.
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.
Baker
M
M
Laboratory of Lymphocyte Signalling and Development, Programme of Molecular Immunology, The Babraham Institute, Cambridge CB2 4AT, UK.
Gamble
J
J
Tooze
R
R
Higgins
D
D
Yang
F T
FT
O'Brien
P C
PC
Coleman
N
N
Pingel
S
S
Turner
M
M
Alexander
D R
DR
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
D017931:DNA Primers; D045522:Recombinases; D011505:Protein-Tyrosine Kinases; D004254:DNA Nucleotidyltransferases; D019426:Integrases; C115006:integron integrase IntI1; D017493:Leukocyte Common Antigens