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

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2001; 276(18):14675-84. DOI: 10.1074/jbc.M008343200
Source: PubMed


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.

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