A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly

Nat Cell Biol. 2014 Jun;16(6):574-86. doi: 10.1038/ncb2972. Epub 2014 May 25.

Abstract

Rho family GTPases control cell migration and participate in the regulation of cancer metastasis. Invadopodia, associated with invasive tumour cells, are crucial for cellular invasion and metastasis. To study Rac1 GTPase in invadopodia dynamics, we developed a genetically encoded, single-chain Rac1 fluorescence resonance energy (FRET) transfer biosensor. The biosensor shows Rac1 activity exclusion from the core of invadopodia, and higher activity when invadopodia disappear, suggesting that reduced Rac1 activity is necessary for their stability, and Rac1 activation is involved in disassembly. Photoactivating Rac1 at invadopodia confirmed this previously unknown Rac1 function. We describe here an invadopodia disassembly model, where a signalling axis involving TrioGEF, Rac1, Pak1, and phosphorylation of cortactin, causes invadopodia dissolution. This mechanism is critical for the proper turnover of invasive structures during tumour cell invasion, where a balance of proteolytic activity and locomotory protrusions must be carefully coordinated to achieve a maximally invasive phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Animals
  • Biosensing Techniques
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement*
  • Cell Surface Extensions / enzymology*
  • Cell Surface Extensions / pathology
  • Cortactin / metabolism
  • Extracellular Matrix / metabolism
  • Female
  • Fluorescence Resonance Energy Transfer
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Neoplasm Invasiveness
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Rats
  • Signal Transduction*
  • Time Factors
  • Transfection
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • CTTN protein, human
  • Cortactin
  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • RAC1 protein, human
  • Trio protein, rat
  • PAK1 protein, human
  • Pak1 protein, rat
  • Protein-Serine-Threonine Kinases
  • TRIO protein, human
  • p21-Activated Kinases
  • Rac1 protein, rat
  • rac1 GTP-Binding Protein