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Imaging G-protein Coupled Receptor GPCR-mediated Signaling Events that Control Chemotaxis of Dictyostelium Discoideum
09:40

Imaging G-protein Coupled Receptor GPCR-mediated Signaling Events that Control Chemotaxis of Dictyostelium Discoideum

Published on: September 20, 2011

18.5K

GPCR-controlled membrane recruitment of negative regulator C2GAP1 locally inhibits Ras signaling for adaptation and

Xuehua Xu1, Xi Wen2, Douwe M Veltman3

  • 1Chemotaxis Signaling Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; XXU@niaid.nih.gov.

Proceedings of the National Academy of Sciences of the United States of America
|November 8, 2017
PubMed

Insights

Scientists discovered C2GAP1, a protein that inhibits Ras signaling, which is crucial for eukaryotic cells to adapt and maintain directional movement (chemotaxis) in response to chemical signals.

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Eukaryotic cells exhibit chemotaxis, navigating chemical gradients by balancing response activation and adaptation.
  • Understanding the molecular mechanisms of inhibitory processes in chemotaxis is crucial for adaptation and sensitivity.
  • G protein-coupled receptor (GPCR)-mediated signaling networks are central to chemotaxis but their inhibitory components remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms of inhibitory processes in GPCR-mediated chemotaxis.
  • To identify novel regulators of Ras signaling involved in chemotaxis adaptation.
  • To investigate the role of C2GAP1 in regulating Ras signaling and cell behavior during chemotaxis.

Main Methods:

  • Utilized *Dictyostelium discoideum* as a model organism for studying chemotaxis.
  • Investigated the localization and function of C2GAP1 using biochemical and cell imaging techniques.
  • Analyzed Ras signaling activation, actin polymerization, and chemotactic behavior in wild-type and C2GAP1-deficient cells.

Main Results:

  • Identified C2GAP1 as a novel, locally acting negative regulator of Ras signaling at the leading edge of chemotaxing cells.
  • Demonstrated that C2GAP1 requires both C2 and GAP domains for membrane localization and is recruited/retained by GPCR-triggered Ras activation.
  • C2GAP1 deficiency leads to aberrant Ras activation, impaired gradient sensing, excessive F-actin polymerization, and defective chemotaxis, with concentration-dependent effects.

Conclusions:

  • Uncovered a locally controlled inhibitory mechanism involving C2GAP1 essential for adaptation in GPCR-mediated chemotaxis.
  • C2GAP1 plays a critical role in regulating Ras signaling to ensure proper gradient sensing and long-range directional cell movement.
  • This finding provides new insights into the molecular basis of chemotaxis adaptation and sensitivity in eukaryotic cells.
Keywords:
G protein-coupled receptorRas GAPRas activationadaptationchemotaxis

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