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Regulation of the DLC3 tumor suppressor by a novel phosphoswitch

Yannick Frey1, Cristiana Lungu1,2, Florian Meyer1

  • 1University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany.

Iscience
|July 18, 2024
PubMed

Insights

Deleted in liver cancer 3 (DLC3), a RhoGAP protein, uses a polybasic region to bind membranes. Phosphorylation regulates this binding, controlling Rho signaling crucial for cell division.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Deleted in liver cancer 3 (DLC3) is a Rho GTPase-activating protein (RhoGAP) essential for cell adhesion and vesicle transport.
  • DLC3 regulates Rho activity at cellular membranes, impacting cell polarity and integrity.

Purpose of the Study:

  • To identify novel mechanisms regulating DLC3 localization and function.
  • To investigate the role of DLC3 in Rho signaling termination and cell division.

Main Methods:

  • Bioinformatical sequence analysis of DLC3.
  • In vitro and in cellulo assays to study protein-membrane interactions.
  • Site-directed mutagenesis to assess the impact of phosphorylation.

Main Results:

  • A polybasic region (PBR) in DLC3 was identified, mediating its association with cellular membranes.
  • Phosphorylation of two serine residues within the PBR alters its electrostatic properties and impairs membrane binding.
  • DLC3 localizes to the midbody, where it regulates Rho activity in a PBR-dependent manner, crucial for cytokinesis.

Conclusions:

  • DLC3 membrane association is regulated by phosphorylation of its polybasic region.
  • This phosphorylation-dependent mechanism enables spatiotemporal control of Rho signaling by DLC3.
  • DLC3 plays a critical role in regulating Rho activity during cytokinesis.
Keywords:
Cell biologyMolecular interactionProteomics

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