Transcriptionally Inducible Pleckstrin Homology-like Domain, Family A, Member 1, Attenuates ErbB Receptor Activity by Inhibiting Receptor Oligomerization

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2017 Dec 14

PMID 29233889

Citations 8

Authors

Shigeyuki Magi

Kazunari Iwamoto

Noriko Yumoto

Michio Hiroshima

Takeshi Nagashima

Rieko Ohki

Amaya Garcia-Munoz

Natalia Volinsky

Alexander von Kriegsheim

Yasushi Sako

Koichi Takahashi

Shuhei Kimura

Boris N Kholodenko

Mariko Okada-Hatakeyama

Affiliations

Soon will be listed here.

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 expression in MCF-7 cells. Transcriptionally-induced PHLDA1 protein directly binds to ErbB3, whereas knockdown of 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.

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