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  • The EMBO Journal (2003) 22, 252 - 261
  • doi:10.1093/emboj/cdg021

POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis

Zhiheng Xu1,2, Nickolay V. Kukekov1,2 and Lloyd A. Greene1

  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

Correspondence to:

Lloyd A. Greene, E-mail: lag3@columbia.edu

Received 17 June 2002; Accepted 14 November 2002; Revised 6 November 2002

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.

  • Keywords:

    • apoptosis,
    • JNKs,
    • MLKs,
    • POSH,
    • protein scaffold