Hematopoietic progenitor kinase 1 supports apoptosis of T lymphocytes.
Hematopoietic progenitor kinase 1 (HPK1) is a member of germinal center kinases that is predominantly expressed in hematopoietic cells and transiently activated by T-cell receptor (TCR) triggering. We show here that HPK1 supports apoptosis of T cells. When HPK1 was overexpressed in murine CD4(+) T cells, a substantial increase was observed in spontaneous and TCR/CD3-mediated apoptosis as well as in Fas ligand (FasL) expression. In H2O2-treated EL-4 thymoma cells, which show an increase in reactive oxygen species (ROS) and apoptosis, overexpression of HPK1 enhanced ROS-mediated apoptosis, whereas expression of HPK1 antisense (AS) RNA impaired apoptosis. HPK1 expression also led to a sustained increase in c-Jun N-terminal kinase (JNK) activity, suggesting that JNK activation contributes to the HPK1-mediated apoptosis in H2O2-treated EL-4 cells. Under the same conditions, a rapid cleavage of HPK1 was observed, and overexpression of N- and C-terminal cleavage products in CD4(+) T cells resulted in, similar to full-length HPK1, an increase in apoptosis. In agreement with published data, we show that the C-terminal portion of HPK1 suppresses IkappaBalpha degradation, thereby inhibiting nuclear factor (NF)-kappaB activation. These findings suggest that by inhibiting the antiapoptotic action of NF-kappaB and inducing the proapoptotic activity of JNK, OHPK1 supports apoptosis in T cells.
Department of Molecular Pathology, Institute of Pathology, D-97080 Wuerzburg, Germany.
Jan
J
Schulze-Luehrmann
Brigitte
B
Santner-Nanan
Mithilesh Kumar
MK
Jha
Anneliese
A
Schimpl
Andris
A
Avots
Edgar
E
Serfling
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D014162:Transfection; D014407:Tumor Cells, Cultured
D017252:CD3 Complex; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases