A novel specific role for I kappa B kinase complex-associated protein in cytosolic stress signaling.
We demonstrate here a novel role for the I kappa B kinase complex-associated protein (IKAP) in the regulation of activation of the mammalian stress response via the c-Jun N-terminal kinase (JNK)-signaling pathway. We cloned IKAP as a JNK-associating protein using the Ras recruitment yeast two-hybrid system. IKAP efficiently and specifically enhanced JNK activation induced by ectopic expression of MEKK1 and ASK1, upstream activators of JNK. Importantly, IKAP also enhanced JNK activation induced by ultraviolet light irradiation as well as treatments with tumor necrosis factor or epidermal growth factor. The JNK association site in IKAP was mapped to the C-terminal part of IKAP. Interestingly, this region is deleted from IKAP expressed in the autonomous nervous system of the patients affected by familial dysautonomia. Ectopic expression of this C-terminal fragment of IKAP was sufficient to support JNK activation. Taken together, our data demonstrate a novel role for IKAP in the regulation of the JNK-mediated stress signaling. Additionally, our results point to a role of JNK signaling in familial dysautonomia and, thus, further support the involvement of JNK signaling in the development, survival, and degeneration of the sensory and autonomic nervous system.
Holmberg
Christian
C
Apoptosis Laboratory, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Katz
Sigal
S
Lerdrup
Mads
M
Herdegen
Thomas
T
Jäättelä
Marja
M
Aronheim
Ami
A
Kallunki
Tuula
T
D001483:Base Sequence; D003001:Cloning, Molecular; D003600:Cytosol / Q000502:physiology*; D017931:DNA Primers; D018076:DNA, Complementary; D006801:Humans; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016296:Mutagenesis; D016133:Polymerase Chain Reaction / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015183:Restriction Mapping; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological
D017931:DNA Primers; D018076:DNA, Complementary; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases