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CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway

Youssef Aissouni1, Grzegorz Zapart, Juan L Iovanna

  • 1INSERM, U.624, 13288 Marseille, France.

Biochemical and Biophysical Research Communications
|November 1, 2005
PubMed

Insights

The CIN85 protein interacts with MEKK4, enhancing the p38 MAP kinase pathway activation during cellular stress. This interaction is crucial for regulating cellular stress responses through MAPK pathways.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Signal Transduction

Background:

  • CIN85 (Cbl-interacting protein of 85 kDa) is a multi-adaptor protein regulating receptor tyrosine kinases and neuronal cell survival.
  • It possesses three SH3 domains that bind proline-arginine motifs (PxxxPR) in effector proteins.

Purpose of the Study:

  • To identify and characterize novel CIN85-interacting partners.
  • To elucidate the role of CIN85 in the regulation of MAPK pathways, particularly in response to cellular stress.

Main Methods:

  • Co-immunoprecipitation assays to confirm protein-protein interactions.
  • In vitro binding assays to map interaction domains.
  • Western blotting to assess protein activation and ubiquitination.
  • Stimulation assays using oxidative stress and growth factors.

Main Results:

  • MEKK4 (MAP kinase kinase kinase 4) was identified as a novel binding partner of CIN85.
  • The interaction is mediated by CIN85 SH3 domains binding to three PxxxPR motifs in MEKK4.
  • CIN85 binding to MEKK4 enhances MKK6 and p38 MAP kinase activation following oxidative stress and growth factor stimulation.
  • CIN85 regulates MEKK4 activation by GADD45 proteins and promotes MEKK4 multi-ubiquitination.

Conclusions:

  • CIN85 plays a novel role in regulating cellular stress responses.
  • CIN85 modulates MAPK pathway signaling through its interaction with MEKK4.
  • This interaction is critical for the cellular response to oxidative stress and growth factor signaling.

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