Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis.
Siah proteins are ubiquitin-protein isopeptide ligases (E3) that have been implicated in a variety of cellular actions, including promotion of apoptotic death. Here, we show that Siah1 is a binding partner for POSH (plenty of SH3s), a scaffold component of the apoptotic JNK pathway, and that Siah contributes to death of neurons and other cell types by activating the JNK pathway. Such proapoptotic activity requires the E3 ligase activity of Siah1. Moreover, apoptotic stimuli markedly elevate cellular Siah1 levels by a mechanism reliant on Siah1 protein stabilization. This stabilization requires JNK pathway activation and interaction with POSH and is enhanced by phosphorylation of SIAH1 at tyrosines 100 and 126. Depletion of intracellular Siah proteins via small interference RNA partially protects cells from death evoked by apoptotic stimuli such as trophic factor deprivation and DNA damage. These findings thus reveal a "loop" mechanism in which the JNK pathway promotes SIAH1 stabilization and in which SIAH1 in turn activates the JNK pathway and, ultimately, contributes to cell death.
Xu
Zhiheng
Z
Department of Pathology and Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. zhxu@genetics.ac.cn
Sproul
Andrew
A
Wang
Wenyi
W
Kukekov
Nikolay
N
Greene
Lloyd A
LA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers / Q000502:physiology; D000098563:Seven in Absentia Proteins
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D011506:Proteins; C111370:Sh3md2 protein, mouse; D014443:Tyrosine; C484442:Siah1a protein, mouse; C484443:Siah1b protein, mouse; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D048031:JNK Mitogen-Activated Protein Kinases