The Src-selective kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine kinases.

2.50
Hdl Handle:
http://hdl.handle.net/10541/79135
Title:
The Src-selective kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine kinases.
Authors:
Tatton, Louise; Morley, Gary M; Chopra, Rajesh; Khwaja, Asim
Abstract:
4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]- pyrimidine (PP1) was identified as an Src-selective tyrosine kinase inhibitor and has been used extensively to investigate signaling 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 signaling, 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 mitogen-activated protein 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 4-amino-5- (4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (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 leukemia 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 signal transducer and activators of transcription 5 and mitogen-activated protein kinase and triggered apoptosis in FDCP1 cells expressing Bcr-Abl. These results have implications for the use of PP1 in investigating intracellular signaling 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.
Affiliation:
Department of Haematology, Royal Free and University College Medical School, 98 Chenies Mews, London WC1E 6HX, United Kingdom.
Citation:
The Src-selective kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine kinases. 2003, 278 (7):4847-53 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
14-Feb-2003
URI:
http://hdl.handle.net/10541/79135
DOI:
10.1074/jbc.M209321200
PubMed ID:
12475982
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorTatton, Louise-
dc.contributor.authorMorley, Gary M-
dc.contributor.authorChopra, Rajesh-
dc.contributor.authorKhwaja, Asim-
dc.date.accessioned2009-08-28T12:13:09Z-
dc.date.available2009-08-28T12:13:09Z-
dc.date.issued2003-02-14-
dc.identifier.citationThe Src-selective kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine kinases. 2003, 278 (7):4847-53 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid12475982-
dc.identifier.doi10.1074/jbc.M209321200-
dc.identifier.urihttp://hdl.handle.net/10541/79135-
dc.description.abstract4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]- pyrimidine (PP1) was identified as an Src-selective tyrosine kinase inhibitor and has been used extensively to investigate signaling 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 signaling, 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 mitogen-activated protein 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 4-amino-5- (4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (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 leukemia 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 signal transducer and activators of transcription 5 and mitogen-activated protein kinase and triggered apoptosis in FDCP1 cells expressing Bcr-Abl. These results have implications for the use of PP1 in investigating intracellular signaling 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.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshCell Line-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshMutation-
dc.subject.meshProtein-Tyrosine Kinases-
dc.subject.meshProto-Oncogene Proteins c-kit-
dc.subject.meshPyrazoles-
dc.subject.meshPyrimidines-
dc.subject.meshRats-
dc.subject.meshSignal Transduction-
dc.subject.meshsrc-Family Kinases-
dc.titleThe Src-selective kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine kinases.en
dc.typeArticleen
dc.contributor.departmentDepartment of Haematology, Royal Free and University College Medical School, 98 Chenies Mews, London WC1E 6HX, United Kingdom.en
dc.identifier.journalThe Journal of Biological Chemistryen
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