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Phosphorylated K-Ras limits cell survival by blocking Bcl-xL sensitization of inositol trisphosphate receptors

Pamela J Sung1, Frederick D Tsai, Horia Vais

  • 1New York University (NYU) Cancer Institute, NYU School of Medicine, New York, NY 10016.

Proceedings of the National Academy of Sciences of the United States of America
|December 4, 2013
PubMed

Insights

Phosphorylated K-Ras4B disrupts calcium signaling by binding inositol trisphosphate receptors, leading to cell death. This interaction antagonizes survival signals, revealing a novel toxicity mechanism for K-Ras4B.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • K-Ras4B localization to the plasma membrane is regulated by farnesylation and a polybasic domain.
  • Protein kinase C (PKC) phosphorylation of K-Ras4B at serine 181 induces its translocation to internal membranes.

Purpose of the Study:

  • To elucidate the mechanism underlying phospho-K-Ras4B-induced cellular toxicity.
  • To identify the specific molecular interactions and pathways involved in K-Ras4B-mediated cell death.

Main Methods:

  • Characterization of K-Ras4B translocation upon phosphorylation.
  • Investigation of K-Ras4B interactions with endoplasmic reticulum (ER) proteins, including inositol trisphosphate receptors (IP3Rs).
  • Assessment of calcium flux between ER and mitochondria and its regulation by Bcl-xL and K-Ras4B.

Main Results:

  • Phosphorylated K-Ras4B (phospho-K-Ras4B) translocates from the plasma membrane to the ER and outer mitochondrial membrane, inducing cell death.
  • GTP-bound phospho-K-Ras4B binds to IP3Rs on the ER in a Bcl-xL-dependent manner.
  • This interaction inhibits Bcl-xL's ability to facilitate calcium flux from the ER to mitochondria, impairing respiration, autophagy inhibition, and cell survival.

Conclusions:

  • Inositol trisphosphate receptors are identified as novel effectors of K-Ras4B.
  • Phospho-K-Ras4B antagonizes prosurvival signals by disrupting ER-mitochondrial calcium signaling via IP3Rs.
  • This mechanism provides a new understanding of K-Ras4B toxicity and its role in cell death pathways.
Keywords:
cancermembrane proteinoncogene

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