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Updated: Mar 22, 2026

Strategic Endothelial Cell Tube Formation Assay: Comparing Extracellular Matrix and Growth Factor Reduced Extracellular Matrix
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mTORC2 mediates CXCL12-induced angiogenesis.

Mary E Ziegler1, Michaela M S Hatch1, Nan Wu1

  • 1The Department of Molecular Biology and Biochemistry, University of California Irvine, 3219 McGaugh Hall, Mail Code: 3900, Irvine, CA, 92697, USA.

Angiogenesis
|April 24, 2016
PubMed
Summary

The chemokine CXCL12/CXCR4 pathway promotes angiogenesis via mTORC2, not mTORC1. Inhibiting mTORC2 significantly reduces tumor growth and angiogenesis, highlighting its role in metabolic regulation and vascularization.

Keywords:
AktAngiogenesisCXCL12CXCR4mTORmTORC2

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The chemokine CXCL12, via its receptor CXCR4, is known to promote angiogenesis by enhancing endothelial cell (EC) migration and tube formation.
  • However, the specific downstream signaling pathways in ECs and the upstream activators of mTORC2 signaling in ECs remain largely undefined.

Purpose of the Study:

  • To elucidate the downstream signaling pathways regulated by CXCL12/CXCR4 in angiogenesis.
  • To investigate the role of mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) in CXCL12-mediated angiogenesis and its potential link to metabolic regulation.

Main Methods:

  • Utilized in vitro 3D angiogenesis models with endothelial cells and in vivo mouse tumor models.
  • Employed pharmacological inhibitors and small interfering RNAs (siRNAs) to selectively disrupt mTORC1 and mTORC2 signaling.
  • Assessed endothelial cell migration, tube formation, microvascular sprouting, tumor angiogenesis, and tumor volume.
  • Investigated signaling pathways including Akt phosphorylation, G-protein, phosphatidylinositol 3-kinase (PI3K), and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) expression.

Main Results:

  • CXCL12/CXCR4 signaling activates mTORC2, evidenced by Akt phosphorylation at serine 473, through a G-protein and PI3K-dependent pathway.
  • mTORC2, but not mTORC1, is essential for microvascular sprouting in vitro, as demonstrated by drug and siRNA disruption.
  • In vivo, inhibition of mTORC2 significantly reduces both tumor angiogenesis and tumor volume in a mouse model.
  • PFKFB3, a key regulator of glycolytic flux, is required for in vitro sprouting and its expression is downregulated in vivo upon mTORC2 targeting.

Conclusions:

  • CXCL12-mediated angiogenesis critically requires mTORC2 signaling, independent of mTORC1.
  • mTORC2 acts as a central signaling hub downstream of CXCL12/CXCR4, linking metabolic regulation (via PFKFB3) to angiogenesis.
  • Targeting mTORC2 presents a promising therapeutic strategy for inhibiting tumor angiogenesis and growth.