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Updated: Oct 9, 2025

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RalGPS2 Interacts with Akt and PDK1 Promoting Tunneling Nanotubes Formation in Bladder Cancer and Kidney Cells

Alessia D'Aloia1, Edoardo Arrigoni1, Barbara Costa1

  • 1Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.

Cancers
|December 24, 2021
PubMed

Insights

RalGPS2 protein orchestrates the formation of tunneling nanotubes (TNTs), a cell communication mechanism crucial for cancer progression. Stress conditions enhance RalGPS2 expression, promoting TNTs assembly in cancer cells.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Biology

Background:

  • Tunneling nanotubes (TNTs) are critical for intercellular communication in the tumor microenvironment, influencing cancer progression and metastasis.
  • The precise molecular mechanisms governing TNT formation remain incompletely understood.
  • RalGPS2, a guanine nucleotide exchange factor, has been previously implicated in TNT formation in bladder cancer cells.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying TNT formation mediated by RalGPS2.
  • To investigate the role of RalGPS2 in intercellular communication via TNTs in bladder cancer.
  • To identify proteins interacting with RalGPS2 involved in TNT biogenesis.

Main Methods:

  • Confocal fluorescence time-lapse microscopy was employed to observe TNTs and protein trafficking.
  • Mid and high-stage bladder cancer cell lines (5637) and HEK293 cells were utilized.
  • Co-immunoprecipitation assays were performed to identify protein interactions.

Main Results:

  • Mid and high-stage bladder cancer cells form functional TNTs capable of transferring mitochondria.
  • RalGPS2 is essential for TNT generation, with its expression upregulated under stress conditions.
  • RalGPS2 mediates the trafficking of RalA and leukocyte-specific transcript 1 (LST1) via TNTs.
  • RalGPS2 forms a complex with Akt, PDK1, LST1, and RalA, promoting TNT formation.

Conclusions:

  • RalGPS2 plays a pivotal role in orchestrating the assembly of multimolecular complexes essential for TNT formation.
  • These findings reveal a novel mechanism by which RalGPS2 facilitates intercellular communication and potentially contributes to cancer progression through TNTs.
Keywords:
AktPDK1RalGPS2bladder cancerkidneymicroenvironmentstress conditiontunneling nanotubes

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