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

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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Zhiheng Xu1, Nickolay V Kukekov, Lloyd A Greene

  • 1Department of Pathology and Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

The EMBO Journal
|January 7, 2003
PubMed

Insights

The protein POSH acts as a scaffold, organizing the JNK pathway crucial for neuronal death. It links activated Rac1 to downstream components, influencing programmed cell death in neurons.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • The c-Jun N-terminal kinase (JNK) pathway is implicated in programmed neuronal death.
  • Scaffold proteins play critical roles in signal transduction by organizing signaling complexes.
  • The protein POSH (plenty of SH3s) is a multidomain protein with known interactions in signaling pathways.

Purpose of the Study:

  • To investigate the role of POSH as a scaffold protein in the JNK pathway of neuronal death.
  • To elucidate the specific interactions of POSH within the JNK signaling cascade.
  • To determine the functional significance of POSH in mediating neuronal apoptosis.

Main Methods:

  • Co-immunoprecipitation assays to assess protein-protein interactions in vivo and in vitro.
  • Overexpression studies using dominant-negative constructs and inhibitors to probe pathway function.
  • Application of antisense oligonucleotides and small interfering RNA (siRNA) to reduce POSH levels.
  • Assessment of c-Jun phosphorylation and neuronal apoptosis as readouts of pathway activity.

Main Results:

  • POSH directly binds to mixed-lineage kinases (MLKs) and complexes with MAP kinase kinases (MKKs) 4/7 and c-Jun N-terminal kinases (JNKs).
  • Overexpression of POSH enhances apoptotic neuronal death, which can be blocked by inhibiting downstream JNK pathway components.
  • Silencing POSH expression using antisense or siRNA suppresses c-Jun phosphorylation and neuronal apoptosis induced by nerve growth factor (NGF) deprivation.
  • POSH acts as a central scaffold, linking activated Rac1/Cdc42 to the downstream JNK apoptotic cascade.

Conclusions:

  • POSH functions as a critical scaffold protein within the JNK signaling pathway, facilitating neuronal apoptosis.
  • POSH integrates upstream signals (activated Rac1) with downstream JNK cascade effectors, promoting programmed neuronal death.
  • Targeting POSH may offer a therapeutic strategy for conditions involving excessive neuronal death.

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