Hematopoietic progenitor kinase 1 supports apoptosis of T lymphocytes

Department of Molecular Pathology, Institute of Pathology, D-97080 Wuerzburg, Germany.
Blood (Impact Factor: 10.45). 09/2002; 100(3):954-60. DOI: 10.1182/blood-2002-01-0089
Source: PubMed


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.

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    • "As with MST kinases, cleavage by caspase-3 at the hinge region (DDVD 385 ↓I) separates these domains of HPK1, resulting in kinase activation (Chen et al., 1999; Arnold et al., 2001) (Figure 2). Importantly, the cleaved catalytic fragment is still capable of activating the JNK pathway, but not NF-κB signaling (Chen et al., 1999; Arnold et al., 2001; Schulze-Luehrmann et al., 2002). "
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    • "Like other serine/threonine phosphatases, PP4 is probably targeted to its specific sites of action by these regulatory subunits and it is likely that the interchange between the different regulatory subunits and binding proteins plays a critical role in regulating the activity of PP4 complexes. It is also important to note that PP4c is a positive regulator of HPK1 [38], which in turn is known to promote apoptosis of murine T lymphocytes [57,58]. The possibility that over-expression of PP4c promotes apoptosis via the activation of HPK1 therefore requires further investigation. "
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    • "Although initial stimulation of peripheral primary T cells leads to proliferation, restimulation of expanded T cells results in AICD. The hematopoietic progenitor kinase (HPK) 1 was characterized as an immunoreceptor proximal signaling protein (Liou et al., 2000) involved in the regulation of AICD in primary T cells (Brenner et al., 2005; Schulze-Luehrmann et al., 2002). Although the full-length serine-threonine kinase is activated by AgR engagement and recruited into lipid rafts, where it has been shown to activate JNK and enhance IKKb phosphorylation, the C-terminal HPK1 cleavage product that is generated in AICD-sensitive primary T cells sequesters the IKK complex by binding to IKKa- IKKb, and its binding thus leads to inhibition of TCRmediated NF-kB activation (Brenner et al., 2005). "
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