Endoplasmic reticulum-plasma membrane contact gradients direct cell migration

  • Nature. 2024 Jun 12. doi: 10.1038/s41586-024-07527-5.
Bo Gong  1  2 ,  Jake D Johnston  3  4 ,  Alexander Thiemicke  5  6 ,  Alex de Marco  4  7 ,  Tobias Meyer  8  9
Affiliations
  • 1. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. [email protected].
  • 2. Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA. [email protected].
  • 3. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
  • 4. Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA.
  • 5. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.
  • 6. Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
  • 7. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
  • 8. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. [email protected].
  • 9. Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA. [email protected].
PMID: 38867038 DOI: 10.1038/s41586-024-07527-5
Abstract

Directed cell migration is driven by the front-back polarization of intracellular signalling1-3. Receptor Tyrosine Kinases and Other inputs activate local signals that trigger membrane protrusions at the front2,4-6. Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts7-9. However, the identity of this mechanism is unknown. Here we report that endoplasmic reticulum-plasma membrane (ER-PM) contact sites are polarized in single and collectively migrating cells. The increased density of these ER-PM contacts at the back provides the ER-resident PTP1B Phosphatase more access to PM substrates, which confines receptor signalling to the front and directs cell migration. Polarization of the ER-PM contacts is due to microtubule-regulated polarization of the ER, with more RTN4-rich curved ER at the front and more CLIMP63-rich flattened ER at the back. The resulting ER curvature gradient leads to small and unstable ER-PM contacts only at the front. These contacts flow backwards and grow to large and stable contacts at the back to form the front-back ER-PM contact gradient. Together, our study suggests that the structural polarity mediated by ER-PM contact gradients polarizes cell signalling, directs cell migration and prolongs cell migration.

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