Hematopoietic progenitor kinase-1 (HPK1) stress response signaling pathway activates IκB kinases (IKK-α/β) and IKK-β is a developmentally regulated protein kinase

Abstract

Nuclear factor kappa-B (NF-κB) is a pleiotropic transcription factor that plays a central role in the immune and inflammatory responses, and is also involved in controlling viral transcription and apoptosis. A critical control in the activation of NF-κB is the phosphorylation of its inhibitory factor IκBs by IκB kinases (IKK-α and -β). Here, we present experiments addressing the regulation and global expression of murine IKK-β, and localize the IKK-β gene to mouse chromosome 8A3-A4. IKK-β was expressed primarily in the liver, kidney and spleen, and at lower levels in the other adult tissues. While IKK-β was expressed ubiquitously throughout the mouse embryo at 9.5 days, its expression began to be localized to the brain, neural ganglia, neural tube, and liver in the 12.5-day's embryo. At 15.5 days, the expression of IKK-β was further restricted to specific tissues of the embryo, suggesting that IKK-β is a developmentally regulated protein kinase. Interestingly, IKK-β phosphorylated IκB constitutively, whereas IKK-α was not active in the absence of cell stimulation. Moreover, both IKK-α and -β were activated by hematopoietic progenitor kinase-1 (HPK1) and MAPK/ERK kinase kinase-1 (MEKK1) specifically, suggesting that IκB/NF-κB is regulated through the HPK1-MEKK1 stress response signaling pathway.