Endoplasmic reticulum-plasma membrane contact gradients direct cell migration

Area of Science:

• Cell Biology
• Biophysics
• Biochemistry

Background:

• Directed cell migration relies on front-back polarization of intracellular signals.
• A long-range inhibitory mechanism is crucial for preventing multiple signaling fronts but remains unidentified.

Purpose of the Study:

• To identify the long-range inhibitory mechanism that directs cell migration.
• To investigate the role of endoplasmic reticulum-plasma membrane (ER-PM) contacts in cell polarization.

Main Methods:

• Microscopy to observe ER-PM contact polarization in migrating cells.
• Biochemical assays to assess phosphatase activity at ER-PM contacts.
• Genetic manipulation to study the role of ER proteins (RTN4, CLIMP63) and microtubules.

Main Results:

• ER-PM contact sites are polarized in migrating cells, with higher density at the back.
• Increased ER-PM contacts at the back enhance access of PTP1B phosphatase to plasma membrane substrates.
• Microtubule-regulated ER polarization, influenced by RTN4 and CLIMP63, creates an ER curvature gradient, leading to polarized ER-PM contacts.

Conclusions:

• Polarized ER-PM contact gradients are a key mechanism for confining receptor signaling to the cell front.
• This structural polarity directs and prolongs cell migration.
• The study reveals a novel role for ER-PM contacts in regulating cell migration dynamics.