A mechanogenetic toolkit for interrogating cell signaling in space and time

Daeha Seo, Kaden M. Southard, Ji Wook Kim, Hyun Jung Lee, Justin Farlow, Jung Uk Lee, David B. Litt, Thomas Haas, A. Paul Alivisatos, Jinwoo Cheon, Zev J. Gartner, Young Wook Jun

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)

Abstract

Tools capable of imaging and perturbing mechanical signaling pathways with fine spatiotemporal resolution have been elusive, despite their importance in diverse cellular processes. The challenge in developing a mechanogenetic toolkit (i.e., selective and quantitative activation of genetically encoded mechanoreceptors) stems from the fact that many mechanically activated processes are localized in space and time yet additionally require mechanical loading to become activated. To address this challenge, we synthesized magnetoplasmonic nanoparticles that can image, localize, and mechanically load targeted proteins with high spatiotemporal resolution. We demonstrate their utility by investigating the cell-surface activation of two mechanoreceptors: Notch and E-cadherin. By measuring cellular responses to a spectrum of spatial, chemical, temporal, and mechanical inputs at the single-molecule and single-cell levels, we reveal how spatial segregation and mechanical force cooperate to direct receptor activation dynamics. This generalizable technique can be used to control and understand diverse mechanosensitive processes in cell signaling.

Original languageEnglish
Pages (from-to)1507-1518
Number of pages12
JournalCell
Volume165
Issue number6
DOIs
Publication statusPublished - 2016 Jun 2

Bibliographical note

Funding Information:
The authors thank S. Blacklow (Harvard University) for the generous gift of Notch plasmids, Y. J. Lim for magnetic nanoparticle synthesis, and the Marvell Nanofabrication Laboratory for use of electron microscope facilities. This work was supported by grant 1R01GM112081-01 from the National Institute of General Medical Science (NIGMS) (Y.J.), a UCSF/UCB/LBNL BRAINseed award (Y.J.), grant 1R21EB015088-01 from the National Institute of Biomedical Imaging and Bioengineering (Z.J.G. and Y.J.), grant DP2 HD080351-01 from the National Institute of Child Health and Human Development (Z.J.G.), grant P50 GM081879 from the NIGMS UCSF Center for Synthetic and Systems Biology (Z.J.G.), a Human Frontier Science Program Fellowship (D.S.), grant IBS-R026-D1 from IBS (J.C. and Y.J.), grant 2010-0018286 from the National Creative Research Initiatives Program (J.C.), grant HI08C2149 from the Korea Healthcare Technology R&D Project (J.C.), and a grant from King Abdulaziz City for Science and Technology (A.P.A.).

Funding Information:
The authors thank S. Blacklow (Harvard University) for the generous gift of Notch plasmids, Y. J. Lim for magnetic nanoparticle synthesis, and the Marvell Nanofabrication Laboratory for use of electron microscope facilities. This work was supported by grant 1R01GM112081-01 from the National Institute of General Medical Science (NIGMS) (Y.J.), a UCSF/UCB/LBNL BRAINseed award (Y.J.), the UCSF Program for Breakthrough Biomedical Research-Sandler Foundation (Y.J.) grant 1R21EB015088-01 from the National Institute of Biomedical Imaging and Bioengineering (Z.J.G. and Y.J.), grant DP2 HD080351-01 from the National Institute of Child Health and Human Development (Z.J.G.), grant P50 GM081879 from the NIGMS UCSF Center for Synthetic and Systems Biology (Z.J.G.), a Human Frontier Science Program Fellowship (D.S.), grant IBS-R026-D1 from IBS (J.C. and Y.J.), grant 2010-0018286 from the National Creative Research Initiatives Program (J.C.), grant HI08C2149 from the Korea Healthcare Technology R&D Project (J.C.), and a grant from King Abdulaziz City for Science and Technology (A.P.A.).

Publisher Copyright:
© 2016 Elsevier Inc. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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