title: Caspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1).
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.
authors.affiliation: Department of Microbiology and Immunology, Baylor College of Medicine, M929, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Y R
authors.initials: YR
authors.lastname: Chen
authors.forename: C F
authors.initials: CF
authors.lastname: Meyer
authors.forename: B
authors.initials: B
authors.lastname: Ahmed
authors.forename: Z
authors.initials: Z
authors.lastname: Yao
authors.forename: T H
authors.initials: TH
authors.lastname: Tan
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011994:Recombinant Proteins; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases