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β1 integrin-mediated signaling regulates MT1-MMP phosphorylation to promote tumor cell invasion

Olivia R Grafinger1, Genya Gorshtein1, Tyler Stirling1

  • 1Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada.

Journal of Cell Science
|March 25, 2020
PubMed

Insights

Cancer cells invade by forming invadopodia, requiring the recycling of membrane type 1-matrix metalloproteinase (MT1-MMP). A β1 integrin signaling pathway, involving Src and EGFR, regulates MT1-MMP phosphorylation and promotes cancer cell invasion.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Signaling

Background:

  • Cancer cell invasion of the extracellular matrix (ECM) is facilitated by invadopodia.
  • Matrix metalloproteinases (MMPs), particularly membrane type 1-matrix metalloproteinase (MT1-MMP), are crucial for ECM degradation at invadopodia.
  • MT1-MMP recycling to invadopodia sites is essential for maintaining cancer cell invasiveness.

Purpose of the Study:

  • To investigate the role of β1 integrin-mediated signaling in the regulation of MT1-MMP internalization and phosphorylation.
  • To elucidate the signaling pathway involved in MT1-MMP phosphorylation and its contribution to cancer cell invasion.

Main Methods:

  • Activation of β1 integrin using the P4G11 antibody.
  • Assessment of MT1-MMP phosphorylation and internalization.
  • Analysis of Src and epidermal growth factor receptor (EGFR) phosphorylation and association.
  • Evaluation of cellular invasiveness and invadopodium formation in vitro.

Main Results:

  • Activation of β1 integrin led to MT1-MMP phosphorylation and internalization.
  • Increased cellular invasiveness and invadopodium formation were observed upon β1 integrin activation.
  • β1 integrin activation induced phosphorylation and increased association of Src and EGFR.
  • Src and EGFR were identified as promoters of MT1-MMP phosphorylation at Thr567.

Conclusions:

  • MT1-MMP phosphorylation is regulated by a β1 integrin-Src-EGFR signaling pathway.
  • This pathway promotes the recycling of MT1-MMP to invadopodia, facilitating cancer cell invasion.
  • Targeting this signaling axis could offer therapeutic strategies for invasive cancers.
Keywords:
Extracellular matrixIntegrinInvadopodiaMT1-MMPPhosphorylation

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