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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

Cell cycle- and apoptosis-regulatory protein-1 is involved in apoptosis signaling by epidermal growth factor receptor

Arun K Rishi1, Liyue Zhang2, Yingjie Yu2

  • 1Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201.

The Journal of Biological Chemistry
|March 18, 2006
PubMed

Insights

CARP-1 protein induces apoptosis by activating caspase-9 and p38 MAPK signaling. Tyrosine 192 on CARP-1 is crucial for this apoptosis-inducing function, particularly in response to ERRP treatment.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • CARP-1 is a novel apoptosis inducer involved in signaling pathways.
  • Epidermal growth factor receptor (EGFR)-related protein (ERRP) inhibits EGFR and promotes apoptosis.
  • EGFR tyrosine kinase inhibitors like Iressa also impact apoptosis.

Purpose of the Study:

  • To elucidate the role of CARP-1 in apoptosis signaling.
  • To investigate the interaction between ERRP, CARP-1, and apoptosis.
  • To identify specific domains and residues of CARP-1 critical for its function.

Main Methods:

  • Cell treatments with ERRP, Iressa, and antisense oligonucleotides.
  • Analysis of CARP-1 protein levels and tyrosine phosphorylation.
  • Expression of wild-type and mutant CARP-1 proteins (including truncated and Y192F mutants).
  • Assessment of caspase-9 activation and p38 MAPK phosphorylation.
  • Use of dominant-negative MKK3/MKK6 to inhibit p38 MAPK pathway.

Main Results:

  • ERRP and Iressa treatments increase CARP-1 levels and tyrosine phosphorylation.
  • Depletion of CARP-1 inhibits ERRP-induced apoptosis.
  • A specific subdomain (amino acids 1-198) of CARP-1 induces apoptosis.
  • Substitution of tyrosine 192 to phenylalanine (Y192F) abrogates ERRP-induced apoptosis.
  • Apoptosis mediated by CARP-1 involves activation of caspase-9 and p38 MAPK phosphorylation.
  • Inhibition of p38 MAPK pathway activators (MKK3/MKK6) blocks CARP-1-induced apoptosis.

Conclusions:

  • Tyrosine 192 of CARP-1 is a key target in apoptosis signaling.
  • CARP-1 promotes apoptosis through p38 MAPK and caspase-9 activation.
  • CARP-1 is a critical mediator of ERRP-induced apoptosis.

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