Hematopoietic progenitor kinase 1 is a component of transforming growth factor beta-induced c-Jun N-terminal kinase signaling cascade.

Abstract The c-Jun N-terminal kinase (JNK) signaling pathway is involved in transforming growth factor β (TGF-β) signaling in a variety of cell systems. We report here that hematopoietic progenitor kinase 1 (HPK1), a novel Ste20-like protein serine/threonine kinase, serves as an upstream mediator for the TGF-β-activated JNK1 cascade in 293T cells. TGF-β treatment resulted in a time-dependent activation of HPK1, which was accompanied by similar kinetics of JNK1 activation. The activation of JNK1 by TGF-β was abrogated by a kinase-defective HPK1 mutant but not by a kinase-defective mutant of kinase homologous to Ste20/Sps1. This result indicates that HPK1 is specifically required for TGF-β-induced activation of JNK1. We also found that TGF-β-induced JNK1 activation was blocked by a kinase-defective mutant of TGF-β-activated kinase 1 (TAK1). In addition, interaction between HPK1 and TAK1 was observed in transient transfection assays, and this interaction was enhanced by TGF-β treatment. Both stress-activated protein kinase/extracellular signal-regulated kinase kinase (SEK) and mitogen-activated protein kinase kinase 7 (MKK7) are immediate upstream activators of JNK1. Although SEK and MKK7 acted downstream of TAK1, only a kinase-defective SEK mutant blocked TGF-β-induced activation of JNK1, indicating that the TGF-β signal is relayed solely through SEK, but not MKK7,in vivo. Furthermore, TGF-β-induced activating protein 1 activation was blocked by a HPK1 mutant, as well as by TAK1 and SEK mutants. Taken together, these studies establish a potential cascade of TGF-β-activated interacting kinases beginning with HPK1, a Ste20 homolog, and ending in JNK1 activation: HPK1 → TAK1 → SEK → JNK1.