Caspase-mediated cleavage of hematopoietic progenitor kinase 1 (HPK1) converts an activator of NFκB into an inhibitor of NFκB

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