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| Subject Categories: Signal Transduction | Differentiation & Death |
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| The EMBO Journal
(2003) 22, 252–261, doi:10.1093/emboj/cdg021 |
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| POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis |
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| Zhiheng Xu1, 2, Nickolay V. Kukekov1, 2 and Lloyd A. Greene1 |
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1 Department of Pathology and Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA 2 Z.Xu and N.V.Kukekov contributed equally to this work To whom correspondence should be addressed Lloyd A. Greene, lag3@columbia.edu Received 17 June 2002; Revised 6 November 2002; Accepted 14 November 2002. |
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| Abstract |
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| We report that the multidomain protein POSH (plenty of SH3s) acts as a scaffold for the JNK pathway of neuronal death. This pathway consists of a sequential cascade involving activated Rac1/Cdc42, mixed-lineage kinases (MLKs), MAP kinase kinases (MKKs) 4 and 7, c-Jun N-terminal kinases (JNKs) and c-Jun, and is required for neuronal death induced by various means including nerve growth factor (NGF) deprivation. In addition to binding GTP-Rac1 as described previously, we find that POSH binds MLKs both in vivo and in vitro, and complexes with MKKs 4 and 7 and with JNKs. POSH overexpression promotes apoptotic neuronal death and this is suppressed by dominant-negative forms of MLKs, MKK4/7 and c-Jun, and by an MLK inhibitor. Moreover, a POSH antisense oligonucleotide and a POSH small interfering RNA (siRNA) suppress c-Jun phosphorylation and neuronal apoptosis induced by NGF withdrawal. Thus, POSH appears to function as a scaffold in a multiprotein complex that links activated Rac1 and downstream elements of the JNK apoptotic cascade. |
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| Keywords: apoptosis, JNKs, MLKs, POSH, protein scaffold |
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