Interaction of hematopoietic progenitor kinase 1 and c-abl tyrosine kinasein response to genotoxic stress

The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agen ts and regulates induction of the stress-activated protein kinase/c-Jun N-t erminal kinase (SAPK/JNK). The hematopoietic progenitor kinase 1 (HPK1) has also been shown to act upstream to the SAPK/JNK signaling pathway. We repo rt here that exposure of hematopoietic Jurkat T cells to genotoxic agents i s associated with activation of HPK1. The results demonstrate that exposure of Jurkat cells to DNA-damaging agents is associated with translocation of active c-Abl from nuclei to cytoplasm and binding of c-Abl to HPK1. Our fi ndings also demonstrate that c-Abl phosphorylates HPK1 in cytoplasm and sti mulates HPK1 activity. The functional significance of the c-Abl-HPK1 intera ction is supported by the demonstration that this complex regulates SAPK/JN K activation. Overexpression of c-Abl(K-R) inhibits HPK1-induced activation of SAPK/JNK. Conversely, the dominant negative mutant of HPK1 blocks c-Abl -mediated induction of SAPK/JNK. These findings indicate that activation of HPK1 and formation of HPK1/c-Abl complexes are functionally important in t he stress response of hematopoietic cells to genotoxic agents.