Interaction of hematopoietic progenitor kinase 1 and c-Abl tyrosine kinase in response to genotoxic stress.
The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents and regulates induction of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). The hematopoietic progenitor kinase 1 (HPK1) has also been shown to act upstream to the SAPK/JNK signaling pathway. We report here that exposure of hematopoietic Jurkat T cells to genotoxic agents is 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 findings also demonstrate that c-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. The functional significance of the c-Abl-HPK1 interaction is supported by the demonstration that this complex regulates SAPK/JNK 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 the stress response of hematopoietic cells to genotoxic agents.
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Y
Y
Ito
P
P
Pandey
P
P
Sathyanarayana
P
P
Ling
A
A
Rana
R
R
Weichselbaum
T H
TH
Tan
D
D
Kufe
S
S
Kharbanda
D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D015398:Signal Transduction / Q000528:radiation effects*; D013601:T-Lymphocytes / Q000502:physiology* / Q000528:radiation effects*
C102102:hematopoietic progenitor kinase 1; D016315:Proto-Oncogene Proteins c-abl; D017346:Protein Serine-Threonine Kinases