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

• Published in: The Journal of biological chemistry Vol. 293; no. 6; pp. 2206 - 2218
• Main Authors: Magi, Shigeyuki, Iwamoto, Kazunari, Yumoto, Noriko, Hiroshima, Michio, Nagashima, Takeshi, Ohki, Rieko, Garcia-Munoz, Amaya, Volinsky, Natalia, Von Kriegsheim, Alexander, Sako, Yasushi, Takahashi, Koichi, Kimura, Shuhei, Kholodenko, Boris N., Okada-Hatakeyama, Mariko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.02.2018; American Society for Biochemistry and Molecular Biology
• Subjects: breast cancer; Humans; mathematical modeling; MCF-7 Cells; Models, Chemical; Neuregulin-1 - metabolism; oligomerization; Protein Multimerization; receptor tyrosine kinase; Receptor, ErbB-3 - metabolism; Signal Transduction; Single Molecule Imaging; Single-Cell Analysis; Transcription Factors - metabolism; Transcription Factors - physiology; Transcription, Genetic; mathematical modeling; breast cancer; receptor tyrosine kinase; oligomerization; signal transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M117.778399

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, whereas 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.