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Cleavage of Arrestin3 by Caspases Prevents Apoptosis via Modulation of JNK‐dependent Cell Death Pathway
Author(s) -
Kook Seunghyi,
Gurevich Vsevolod,
Gurevich Eugenia
Publication year - 2010
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.24.1_supplement.485.13
Subject(s) - microbiology and biotechnology , caspase , apoptosis , programmed cell death , mapk/erk pathway , kinase , signal transduction , p38 mitogen activated protein kinases , cleavage (geology) , biology , caspase 2 , chemistry , biochemistry , paleontology , fracture (geology)
Ubiquitously expressed arrestin2 and arrestin3 (ARR3) regulate numerous GPCRs and many other signaling proteins, including key players in life‐or‐death decisions, such as Src, ERK, and JNK. Here we show that arrestin3 is specifically cleaved at Asp366, Asp405 and Asp406 by caspases during apoptosis induced by a variety of stimuli in different cell types. Caspase‐generated ARR3(1–366) dose‐dependently increases the survival of etoposide‐treated cells, whereas caspase‐resistant D366/405/406E mutant significantly facilitates apoptosis. We recently showed that all four vertebrate arrestins bind the three kinases in ASK1‐MKK4‐JNK3 cascade, but only arrestin3 facilitates the activation of pro‐apoptotic JNK3. We found that the deletion of ARR3 C‐terminus by caspases does not prevent JNK3 binding, but abolishes its ability to activate JNK3. In contrast, caspase‐resistant D366/405/406E mutant activates JNK3 as effectively as WT ARR3. Thus, caspase‐generated ARR3(1‐366) prevents signaling in ASK1‐MKK4‐JNK3 cascade and protects cells. These findings demonstrate the involvement of ARR3 in the regulation of apoptotic cell death via JNK3 activity. NIH grants NS065868 (EVG), GM077561, GM081756 (VVG)