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Papers In Press, published online ahead of print December 9, 2002
Department of Haematology, Royal Free and University College Medical School, London WC1E 6HX
Corresponding Author: a.khwaja{at}ucl.ac.uk
PP1 was identified as a Src-selective tyrosine kinase inhibitor and has been used extensively to investigate signalling pathways involving Src kinases including events downstream of the stem cell factor (SCF) receptor c-kit. While investigating the role of Src kinases in SCF signalling we found that PP1 completely abrogated the proliferation of M07e cells in response to SCF. PP1 inhibited SCF-induced c-kit autophosphorylation in intact cells and blocked the activation of MAP kinase and Akt. In vitro kinase assays using immunoprecipitated c-kit confirmed direct inhibition by PP1. SCF-induced c-kit phosphorylation was also inhibited by the related inhibitor PP2 and by STI571 but not by the src inhibitor SU6656. PP1 inhibited the activity of mutant constitutively active forms of c-kit (D814V and D814Y) found in mast cell disorders and triggered apoptosis in the rat basophilic leukaemia cell line RBL-2H3 that expresses mutant c-kit. In addition, PP1 (and PP2) inhibited the in vitro kinase activity and autophosphorylation in whole cells of p210 Bcr-Abl. PP1 reduced the constitutive activation of STAT5 and MAP kinase and triggered apoptosis in FDCP1 cells expressing Bcr-Abl. These results have implications for the use of PP1 in investigating intracellular signalling and suggest that PP1 or related compounds may be useful in the treatment of malignant diseases associated with dysregulated c-kit or abl tyrosine kinase activity.
J. Biol. Chem, 10.1074/jbc.M209321200
Submitted on September 11, 2002
Revised on December 5, 2002
Accepted on December 9, 2002
The Src-selective kinase inhibitor PP1 also inhibits kit and Bcr-Abl tyrosine kinases
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