Transcriptionally inducible Pleckstrin homology-like domain family A member 1 attenuates ErbB receptor activity by inhibiting receptor oligomerization

Shigeyuki Magi, Kazunari Iwamoto, Noriko Yumoto, Michio Hiroshima, Takeshi Nagashima, Rieko Ohki, Amaya Garcia-Munoz, Natalia Volinsky, Alex Von Kriegsheim, Yasushi Sako, Koichi Takahashi, Shuhei Kimura, Boris N Kholodenko, Mariko Okada-Hatakeyama

Research output: Contribution to journalArticlepeer-review

Abstract

Feedback control is a key mechanism in signal transduction, intimately involved in regulating the outcome of the cellular response. Here we report a novel mechanism by which PHLDA1, Pleckstrin homology-like domain, family A, member 1, negatively regulates ErbB receptor signaling by inhibition of receptor oligomerization. We have found that the ErbB3 ligand, heregulin, induces PHILDA1 expression in MCF-7 cells. Transcriptionally-induced PHLDA1 protein directly binds to ErbB3, while knockdown of PHLDA1 increases complex formation between ErbB3 and ErbB2. To provide insight into the mechanism for our time-course and single cell experimental observations, we performed a systematic computational search of network topologies of the mathematical models based on receptor dimer-tetramer formation in the ErbB activation processes. Our results indicate that only a model in which PHLDA1 inhibits formation of both dimers and tetramer can explain the experimental data. Predictions made from this model were further validated by single molecule imaging experiments. Our studies suggest a unique regulatory feature of PHLDA1 to inhibit the ErbB receptor oligomerization process and thereby control the activity of receptor signaling network.

Original languageEnglish
JournalJournal of Biological Chemistry
Early online date12 Dec 2017
DOIs
Publication statusE-pub ahead of print - 12 Dec 2017

Keywords

  • signal transduction
  • breast cancer
  • mathematical modeling
  • receptor tyrosine kinase
  • oligomer

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