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Growth differentiation factor-15 (GDF-15) suppresses in vitro angiogenesis through a novel interaction with

Ramon J Whitson1, Marshall Scott Lucia, James R Lambert

  • 1Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA.

Journal of Cellular Biochemistry
|January 3, 2013
PubMed

Insights

Growth differentiation factor-15 (GDF-15) directly interacts with connective tissue growth factor (CCN2), inhibiting CCN2-driven angiogenesis. This discovery reveals a novel GDF-15 signaling pathway potentially impacting cardiac disease, inflammation, and cancer.

Area of Science:

  • Molecular biology
  • Cell biology
  • Biochemistry

Background:

  • Growth differentiation factor-15 (GDF-15) and connective tissue growth factor (CCN2) are implicated in cardiac disease, inflammation, and cancer.
  • The precise roles and signaling mechanisms of GDF-15 and CCN2 in normal and diseased tissues are not fully understood.

Purpose of the Study:

  • To investigate the interaction between GDF-15 and CCN2.
  • To elucidate the functional consequences and molecular mechanisms of this interaction on angiogenesis.

Main Methods:

  • Yeast two-hybrid assays to detect protein interactions.
  • Biochemical pull-down assays to confirm direct binding.
  • In vitro angiogenesis assays using human umbilical vein endothelial (HUVEC) cells.
  • Examination of αV β3 integrin activation and focal adhesion kinase (FAK) signaling.

Main Results:

  • A direct interaction between GDF-15 and CCN2 was confirmed, localized to the von Willebrand factor type C domain of CCN2.
  • GDF-15 inhibited CCN2-mediated endothelial cell tube formation in vitro.
  • GDF-15 blocked CCN2-induced focal adhesion kinase (FAK) activation.
  • GDF-15 reduced αV β3 integrin clustering in HUVEC cells.

Conclusions:

  • This study demonstrates a novel signaling pathway where GDF-15 interacts with the matricellular protein CCN2.
  • GDF-15 antagonizes CCN2-mediated angiogenesis by inhibiting αV β3 integrin and FAK activation.
  • This interaction provides new insights into the role of GDF-15 in disease pathogenesis.

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