A RAB35-p85/PI3K axis controls oscillatory apical protrusions required for efficient chemotactic migration

Area of Science:

• Cell Biology
• Molecular Biology
• Biophysics

Background:

• Cellular chemotaxis, or directed movement along chemical gradients, is crucial for development and disease.
• Interpreting shallow or noisy chemical signals requires cells to employ excitable processes.
• Circular dorsal ruffles (CDRs) are actin-rich protrusions involved in cell migration.

Purpose of the Study:

• To identify molecular players involved in growth factor-induced chemotaxis.
• To investigate the role of excitable dynamics in cell migration.
• To elucidate the mechanism by which cells steer in response to chemoattractants.

Main Methods:

• High-content screening using RNA interference (RNAi) to identify genes regulating CDR formation.
• Live-cell imaging to observe the dynamics of CDRs and cell migration.
• Molecular assays to investigate the interaction of RAB35 with signaling pathways.

Main Results:

• RAB35 is identified as essential for the formation of growth factor-induced waves of circular dorsal ruffles (CDRs).
• RAB35 is sufficient to induce polarized, propagating waves of CDRs, demonstrating excitable system behavior.
• RAB35 regulates the p85/PI3K polarity axis, crucial for directed cell migration and chemoinvasion.

Conclusions:

• RAB35 acts as a molecular determinant controlling an excitable, oscillatory system.
• This RAB35-mediated system functions as a steering mechanism for growth factor-driven chemotaxis and chemoinvasion.
• The findings provide a new understanding of how cells navigate complex chemical environments.