Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK.
Death-associated protein kinase (DAPK) is a death domain-containing serine/threonine kinase, and participates in various apoptotic paradigms. Here, we identify the extracellular signal-regulated kinase (ERK) as a DAPK-interacting protein. DAPK interacts with ERK through a docking sequence within its death domain and is a substrate of ERK. Phosphorylation of DAPK at Ser 735 by ERK increases the catalytic activity of DAPK both in vitro and in vivo. Conversely, DAPK promotes the cytoplasmic retention of ERK, thereby inhibiting ERK signaling in the nucleus. This reciprocal regulation between DAPK and ERK constitutes a positive feedback loop that ultimately promotes the apoptotic activity of DAPK. In a physiological apoptosis system where ERK-DAPK interplay is reinforced, downregulation of either ERK or DAPK suppresses such apoptosis. These results indicate that bidirectional signalings between DAPK and ERK may contribute to the apoptosis-promoting function of the death domain of DAPK.
Chen
Chun-Hau
CH
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Wang
Won-Jing
WJ
Kuo
Jean-Cheng
JC
Tsai
Hsiao-Chien
HC
Lin
Jia-Ren
JR
Chang
Zee-Fen
ZF
Chen
Ruey-Hwa
RH
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D002384:Catalysis; D002467:Cell Nucleus / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D013379:Substrate Specificity
D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases