Rapid Signal Transduction in Living Cells Is a Unique Feature of Mechanotransduction

Proc Natl Acad Sci U S A. 2008 May 6;105(18):6626-31. doi: 10.1073/pnas.0711704105. Epub 2008 May 2.

Abstract

It is widely postulated that mechanotransduction is initiated at the local force-membrane interface by inducing local conformational changes of proteins, similar to soluble ligand-induced signal transduction. However, all published reports are limited in time scale to address this fundamental issue. Using a FRET-based cytosolic Src reporter in a living cell, we quantified changes of Src activities as a local stress via activated integrins was applied. The stress induced rapid (<0.3 s) activation of Src at remote cytoplasmic sites, which depends on the cytoskeletal prestress. In contrast, there was no Src activation within 12 s of soluble epidermal growth factor (EGF) stimulation. A 1.8-Pa stress over a focal adhesion activated Src to the same extent as 0.4 ng/ml EGF at long times (minutes), and the energy levels for mechanical stimulation and chemical stimulation were comparable. The effect of both stress and EGF was less than additive. Nanometer-scale cytoskeletal deformation analyses revealed that the strong activation sites of Src by stress colocalized with large deformation sites of microtubules, suggesting that microtubules are essential structures for transmitting stresses to activate cytoplasmic proteins. These results demonstrate that rapid signal transduction via the prestressed cytoskeleton is a unique feature of mechanotransduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytoplasm / drug effects
  • Cytoplasm / enzymology
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / pharmacology
  • Humans
  • Integrins / metabolism
  • Mechanotransduction, Cellular* / drug effects
  • Microtubules / drug effects
  • Microtubules / pathology
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Stress, Mechanical
  • Substrate Specificity / drug effects

Substances

  • Actins
  • Integrins
  • Epidermal Growth Factor
  • Proto-Oncogene Proteins pp60(c-src)