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DAPK mediates TNF‐alpha induced apoptosis by TNF‐receptor 1 association and JNK activation through MKK7
Author(s) -
Gentry Patrick Lee,
Zhang Liguo,
Duan Rui,
Gallagher Patricia Jane
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1238.2
Subject(s) - autophosphorylation , microbiology and biotechnology , mapk/erk pathway , kinase , p38 mitogen activated protein kinases , tumor necrosis factor alpha , signal transduction , protein kinase a , chemistry , map kinase kinase kinase , apoptosis , phosphorylation , cancer research , biology , immunology , biochemistry
Death Associated Protein Kinase (DAPK) is a calcium calmodulin (CaM) regulated serine/threonine kinase, which has a pivotal role in regulation of apoptosis and survival in cells. The cellular activities of DAPK are tightly regulated by intracellular calcium levels, an inhibitory autophosphorylation site (S308) within the CaM‐binding domain, and by proteasomal degradation. Preliminary studies from this laboratory have suggested that DAPK has a major role in signaling by the inflammatory cytokine, TNF and becomes associated with TNFR1 in response to TNF. To better understand the mechanism by which DAPK regulates apoptotic responses to the cytokine TNF, we have examined the downstream arms of TNFR1 signaling cascade. These studies have revealed that maximal activation of c‐Jun N‐terminal kinase (JNK) in response to TNF is dependent upon the activities of DAPK. Data shows that upon siRNA mediated depletion of DAPK, JNK 1 activation is significantly attenuated. However, there is no detectable effect on NFkB, p38, or ERK 1/2 activation. This data has identified a novel‐signaling pathway for DAPK, in the regulation of survival, inflammation, and proliferation signals through modulation of MAPK/JNK activation. Ongoing studies are focused on elucidating the mechanism of DAPK activation of the MAPK/JNK pathway and the physiological role of this interaction. Supported by HL54118 and DK062810 to PJG