Transient Acceleration of Epidermal Growth Factor Receptor Dynamics Produces Higher-Order Signaling Clusters |
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Authors: | Michio Hiroshima Chan-gi Pack Kazunari Kaizu Koichi Takahashi Masahiro Ueda Yasushi Sako |
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Institution: | 1. Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-198, Japan;2. Laboratory for Cell Signaling Dynamics, RIKEN QBiC, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan;3. Japan Science and Technology Agency (JST), CREST, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan;4. Asan Institute for Life Sciences, University of Ulsan, College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea;5. Laboratory for Biochemical Simulation, RIKEN QBiC, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan |
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Abstract: | Cell signaling depends on spatiotemporally regulated molecular interactions. Although the movements of signaling proteins have been analyzed with various technologies, how spatial dynamics influence the molecular interactions that transduce signals is unclear. Here, we developed a single-molecule method to analyze the spatiotemporal coupling between motility, clustering, and signaling. The analysis was performed with the epidermal growth factor receptor (EGFR), which triggers signaling through its dimerization and phosphorylation after association with EGF. Our results show that the few EGFRs isolated in membrane subdomains were released by an EGF-dependent increase in their diffusion area, facilitating molecular associations and producing immobile clusters. Using a two-color single-molecule analysis, we found that the EGF-induced state transition alters the properties of the immobile clusters, allowing them to interact for extended periods with the cytoplasmic protein, GRB2. Our study reveals a novel correlation between this molecular interaction and its mesoscale dynamics, providing the initial signaling node. |
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Keywords: | cell signaling regulation membrane subdomain receptor tyrosine kinase single-molecule tracking molecular mobility and clustering EGFR epidermal growth factor receptor GFP green fluorescent protein MSD mean square displacement HMM hidden Markov model VB variational Bayes TMR tetramethylrhodamine FRET fluorescent resonance energy transfer |
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