TY - JOUR
T1 - A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly
AU - Moshfegh, Yasmin
AU - Bravo-Cordero, Jose Javier
AU - Miskolci, Veronika
AU - Condeelis, John
AU - Hodgson, Louis
N1 - Funding Information:
This work was supported by GM093121 (Y.M., J.J.B-C., L.H.), T32GM007491 (Y.M., V.M.), and CA150344 (J.J.B-C., J.C.). We acknowledge G. Rosenberger (Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf Campus, Germany) for providing the α-Pix–GFP construct64, J. van Buul (Sanquin Research and Landsteiner Laboratory, Department of Molecular Cell Biology, Academic Medical Center, University of Amsterdam, The Netherlands) for providing the Trio constructs49, and M. Way (Cell Motility Laboratory, Cancer Research UK, UK) for providing the c-Src constructs65. This work is in partial fulfilment of the PhD requirements for Y.M. We thank the J. Condeelis, J. Segall and D. Cox laboratory members for their helpful discussions.
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
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U2 - 10.1038/ncb2972
DO - 10.1038/ncb2972
M3 - Article
C2 - 24859002
AN - SCOPUS:84901836960
SN - 1465-7392
VL - 16
SP - 571
EP - 583
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 6
ER -