Caspase-mediated cleavage of hematopoietic progenitor kinase 1 (HPK1) converts an activator of NFkappaB into an inhibitor of NFkappaB.
Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related protein kinase, is a potent stimulator of the stress-activated protein kinases (SAPKs/JNKs). Here we report activation of NFkappaB transcription factors by HPK1 that was independent of SAPK/JNK activation. Overexpression of a dominant-negative SEK1 significantly inhibited SAPK/JNK activation, whereas NFkappaB stimulation by HPK1 remained unaffected. Furthermore, activation of NFkappaB required the presence of full-length, kinase-active HPK1, whereas the isolated kinase domain of HPK1 was sufficient for activation of SAPK/JNK. We also demonstrate that overexpression of a dominant-negative IKKbeta blocks HPK1-mediated NFkappaB activation suggesting that HPK1 acts upstream of the IkappaB kinase complex. In apoptotic myeloid progenitor cells HPK1 was cleaved at a DDVD motif resulting in the release of the kinase domain and a C-terminal part. Although expression of the isolated HPK1 kinase domain led to SAPK/JNK activation, the C-terminal part inhibited NFkappaB activation. This dominant-negative effect was not only restricted to HPK1-mediated but also to NIK- and tumor necrosis factor alpha-mediated NFkappaB activation, suggesting an impairment of the IkappaB kinase complex. Thus HPK1 activates both the SAPK/JNK and NFkappaB pathway in hematopoietic cells but is converted into an inhibitor of NFkappaB activation in apoptotic cells.
Max-Planck Institute for Physiological and Clinical Research, W. G. Kerckhoff Institute, Parkstrasse 1, D-61231 Bad Nauheim, Germany.
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R
Arnold
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J
Liou
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HC
Drexler
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A
Weiss
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Kiefer
D000595:Amino Acid Sequence; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D017931:DNA Primers; D018922:HL-60 Cells; D006801:Humans; D006868:Hydrolysis; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D016328:NF-kappa B; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases