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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-01-0089.
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Blood, 1 August 2002, Vol. 100, No. 3, pp. 954-960
IMMUNOBIOLOGY
Hematopoietic progenitor kinase 1 supports apoptosis of T
lymphocytes
Jan Schulze-Luehrmann,
Brigitte Santner-Nanan,
Mithilesh Kumar Jha,
Anneliese Schimpl,
Andris Avots, and
Edgar Serfling
From the Department of Molecular Pathology, Institute
of Pathology, Institute of Virology and Immunobiology, and Molecular
Epigenetics Group, Institute of Medical Radiation and Cell Research
(MSZ), D-97080 Wuerzburg, Germany.
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 I B degradation, thereby inhibiting nuclear factor (NF)-B activation. These
findings suggest that by inhibiting the antiapoptotic action of NF-B
and inducing the proapoptotic activity of JNK, OHPK1 supports apoptosis
in T cells.
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