Caspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1)

2.50
Hdl Handle:
http://hdl.handle.net/10547/302092
Title:
Caspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1)
Authors:
Chen, Yi-Rong; Meyer, Christian F; Ahmed, Bushra Y.; Yao, Zhengbin; Tan, Tse-Hua
Abstract:
Activation of c-Jun N-terminal kinase (JNK) by Fas ligation is caspase-dependent, suggesting that caspases may regulate activators of the JNK pathway. Here, we report that an upstream activator of JNK, hematopoietic progenitor kinase 1 (HPK1), was cleaved during apoptosis. Cleavage of HPK1 was blocked by peptide inhibitors for caspases. HPK1 was efficiently processed by recombinant caspase 3 in vitro. A conserved caspase recognition site, DDVD (amino acids 382 - 385), was found in the HPK1 protein sequence. By testing HPK1 proteins with in vivo and in vitro cleavage assays, we showed that aspartic acid residue 385 is the target for caspases. HPK1 cleavage separated the amino N-terminal kinase domain from the carboxyl C-terminal regulatory domain, and enhanced HPK1 kinase activity. Unlike the full-length HPK1, the N-terminal cleaved product failed to bind adaptor molecules Grb2 (growth factor receptor-bound protein 2) and Crk (CT10 regulator of kinase). The C-terminal fragment, although having three proline-rich domains, bound to Grb2 and Crk less efficiently than the full-length HPK1 protein. Taken together, the cleavage of HPK1 by caspase profoundly changed its biochemical properties.
Citation:
Chen Y-R., Meyer C., Ahmed B. Y., Yao Z. and Tan T-H. (1999) 'Caspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1' Oncogene, 18(51),pp.7370-7377
Publisher:
Nature Publishing Group
Journal:
Oncogene
Issue Date:
1999
URI:
http://hdl.handle.net/10547/302092
DOI:
10.1038/sj.onc.1203116
Additional Links:
http://www.nature.com/doifinder/10.1038/sj.onc.1203116
Type:
Article
Language:
en
ISSN:
0950-9232
Appears in Collections:
Cell and Cryobiology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorChen, Yi-Rongen_GB
dc.contributor.authorMeyer, Christian Fen_GB
dc.contributor.authorAhmed, Bushra Y.en_GB
dc.contributor.authorYao, Zhengbinen_GB
dc.contributor.authorTan, Tse-Huaen_GB
dc.date.accessioned2013-09-23T11:57:04Z-
dc.date.available2013-09-23T11:57:04Z-
dc.date.issued1999-
dc.identifier.citationChen Y-R., Meyer C., Ahmed B. Y., Yao Z. and Tan T-H. (1999) 'Caspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1' Oncogene, 18(51),pp.7370-7377en_GB
dc.identifier.issn0950-9232-
dc.identifier.doi10.1038/sj.onc.1203116-
dc.identifier.urihttp://hdl.handle.net/10547/302092-
dc.description.abstractActivation of c-Jun N-terminal kinase (JNK) by Fas ligation is caspase-dependent, suggesting that caspases may regulate activators of the JNK pathway. Here, we report that an upstream activator of JNK, hematopoietic progenitor kinase 1 (HPK1), was cleaved during apoptosis. Cleavage of HPK1 was blocked by peptide inhibitors for caspases. HPK1 was efficiently processed by recombinant caspase 3 in vitro. A conserved caspase recognition site, DDVD (amino acids 382 - 385), was found in the HPK1 protein sequence. By testing HPK1 proteins with in vivo and in vitro cleavage assays, we showed that aspartic acid residue 385 is the target for caspases. HPK1 cleavage separated the amino N-terminal kinase domain from the carboxyl C-terminal regulatory domain, and enhanced HPK1 kinase activity. Unlike the full-length HPK1, the N-terminal cleaved product failed to bind adaptor molecules Grb2 (growth factor receptor-bound protein 2) and Crk (CT10 regulator of kinase). The C-terminal fragment, although having three proline-rich domains, bound to Grb2 and Crk less efficiently than the full-length HPK1 protein. Taken together, the cleavage of HPK1 by caspase profoundly changed its biochemical properties.en_GB
dc.language.isoenen
dc.publisherNature Publishing Groupen_GB
dc.relation.urlhttp://www.nature.com/doifinder/10.1038/sj.onc.1203116en_GB
dc.rightsArchived with thanks to Oncogeneen_GB
dc.titleCaspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1)en
dc.typeArticleen
dc.identifier.journalOncogeneen_GB
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