Spatial modeling of the membrane-cytosolic interface in protein kinase signal transduction

PLoS Comput Biol. 2018 Apr 9;14(4):e1006075. doi: 10.1371/journal.pcbi.1006075. eCollection 2018 Apr.

Abstract

The spatial architecture of signaling pathways and the interaction with cell size and morphology are complex, but little understood. With the advances of single cell imaging and single cell biology, it becomes crucial to understand intracellular processes in time and space. Activation of cell surface receptors often triggers a signaling cascade including the activation of membrane-attached and cytosolic signaling components, which eventually transmit the signal to the cell nucleus. Signaling proteins can form steep gradients in the cytosol, which cause strong cell size dependence. We show that the kinetics at the membrane-cytosolic interface and the ratio of cell membrane area to the enclosed cytosolic volume change the behavior of signaling cascades significantly. We suggest an estimate of average concentration for arbitrary cell shapes depending on the cell volume and cell surface area. The normalized variance, known from image analysis, is suggested as an alternative measure to quantify the deviation from the average concentration. A mathematical analysis of signal transduction in time and space is presented, providing analytical solutions for different spatial arrangements of linear signaling cascades. Quantification of signaling time scales reveals that signal propagation is faster at the membrane than at the nucleus, while this time difference decreases with the number of signaling components in the cytosol. Our investigations are complemented by numerical simulations of non-linear cascades with feedback and asymmetric cell shapes. We conclude that intracellular signal propagation is highly dependent on cell geometry and, thereby, conveys information on cell size and shape to the nucleus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport, Active
  • Cell Membrane / metabolism
  • Cell Nucleus / metabolism
  • Cell Shape / physiology
  • Cell Size
  • Computational Biology
  • Computer Simulation
  • Cytosol / metabolism
  • Feedback, Physiological
  • Finite Element Analysis
  • Kinetics
  • Models, Biological*
  • Nonlinear Dynamics
  • Protein Kinases / metabolism*
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / physiology*

Substances

  • Receptors, Cell Surface
  • Protein Kinases

Grants and funding

This work was supported by a grant from the German Research Foundation (CRC 740 ‘From molecules to modules’) to EK. GM and AS gratefully acknowledge support from the Sparkling Science research program of the Federal Ministry of Science, Research and Economy of Austria (BMWFW) within the Sparkling Science project “EMMA {Experimentation with mathematical algorithms}” (SPA 05/172). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.