Caspase-mediated Cleavage of Hematopoietic Progenitor Kinase 1 (HPK1) Converts an Activator of NFκB into an Inhibitor of NFκB

Ruediger Arnold, Jen Liou, Hannes C A Drexler, Arthur Weiss, Friedemann Kiefer

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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 NFκB transcription factors by HPK1 that was independent of SAPK/JNK activation. Overexpression of a dominant-negative SEK1 significantly inhibited SAPK/JNK activation, whereas NFκB stimulation by HPK1 remained unaffected. Furthermore, activation of NFκB 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 IKKβ blocks HPK1-mediated NFκB activation suggesting that HPK1 acts upstream of the IκB 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 NFκB activation. This dominant-negative effect was not only restricted to HPK1-mediated but also to NIK-and tumor necrosis factor α-mediated NFκB activation, suggesting an impairment of the IκB kinase complex. Thus HPK1 activates both the SAPK/JNK and NFκB pathway in hematopoietic cells but is converted into an inhibitor of NFκB activation in apoptotic cells.

Original languageEnglish (US)
Pages (from-to)14675-14684
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number18
DOIs
StatePublished - May 4 2001

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Caspases
Chemical activation
Phosphotransferases
Protein Kinases
hematopoietic progenitor kinase 1
Myeloid Progenitor Cells
MAP Kinase Signaling System
Heat-Shock Proteins
Transcription Factors
Tumor Necrosis Factor-alpha
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Caspase-mediated Cleavage of Hematopoietic Progenitor Kinase 1 (HPK1) Converts an Activator of NFκB into an Inhibitor of NFκB. / Arnold, Ruediger; Liou, Jen; Drexler, Hannes C A; Weiss, Arthur; Kiefer, Friedemann.

In: Journal of Biological Chemistry, Vol. 276, No. 18, 04.05.2001, p. 14675-14684.

Research output: Contribution to journalArticle

Arnold, Ruediger ; Liou, Jen ; Drexler, Hannes C A ; Weiss, Arthur ; Kiefer, Friedemann. / Caspase-mediated Cleavage of Hematopoietic Progenitor Kinase 1 (HPK1) Converts an Activator of NFκB into an Inhibitor of NFκB. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 18. pp. 14675-14684.
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