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 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.