A novel spatiotemporal RhoC activation pathway locally regulates cofilin activity at invadopodia

Jose Javier Bravo-Cordero, Matthew Oser, Xiaoming Chen, Robert J. Eddy, Louis Hodgson, John S. Condeelis

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Background: RhoGTPases have been implicated in the regulation of cancer metastasis. Invasive carcinoma cells form invadopodia, F-actin-rich matrix-degrading protrusions that are thought to be important for tumor cell invasion and intravasation. Regulation of actin dynamics at invadopodial protrusions is crucial to drive invasion. This process requires the severing activity of cofilin to generate actin-free barbed ends. Previous work demonstrates that cofilin's severing activity is tightly regulated through multiple mechanisms, including regulation of cofilin serine phosphorylation by Rho GTPases. However, it is not known which Rho GTPase is involved in regulating cofilin's phosphorylation status at invadopodia. Results: We show here, for the first time, how RhoC activation is controlled at invadopodia and how this activation regulates cofilin phosphorylation to control cofilin's generation of actin-free barbed ends. Live-cell imaging of fluorescent RhoC biosensor reveals that RhoC activity is spatially confined to areas surrounding invadopodia. This spatiotemporal restriction of RhoC activity is controlled by "spatially distinct regulatory elements" that confine RhoC activation within this compartment. p190RhoGEF localizes around invadopodia to activate RhoC, whereas p190RhoGAP localizes inside invadopodia to deactivate the GTPase within the structure. RhoC activation enhances cofilin phosphorylation outside invadopodia. Conclusion: These results show how RhoC activity is spatially regulated at invadopodia by p190RhoGEF and p190RhoGAP. RhoC activation in areas surrounding invadopodia restricts cofilin activity to within the invadopodium core, resulting in a focused invadopodial protrusion. This mechanism likely enhances tumor cell invasion during metastasis.

Original languageEnglish (US)
Pages (from-to)635-644
Number of pages10
JournalCurrent Biology
Volume21
Issue number8
DOIs
StatePublished - Apr 26 2011

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Actin Depolymerizing Factors
actin
phosphorylation
guanosinetriphosphatase
Chemical activation
Phosphorylation
cell invasion
metastasis
Actins
rho GTP-Binding Proteins
biosensors
Cells
serine
carcinoma
Tumors
image analysis
cells
neoplasms
Podosomes
GTP Phosphohydrolases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

A novel spatiotemporal RhoC activation pathway locally regulates cofilin activity at invadopodia. / Bravo-Cordero, Jose Javier; Oser, Matthew; Chen, Xiaoming; Eddy, Robert J.; Hodgson, Louis; Condeelis, John S.

In: Current Biology, Vol. 21, No. 8, 26.04.2011, p. 635-644.

Research output: Contribution to journalArticle

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AB - Background: RhoGTPases have been implicated in the regulation of cancer metastasis. Invasive carcinoma cells form invadopodia, F-actin-rich matrix-degrading protrusions that are thought to be important for tumor cell invasion and intravasation. Regulation of actin dynamics at invadopodial protrusions is crucial to drive invasion. This process requires the severing activity of cofilin to generate actin-free barbed ends. Previous work demonstrates that cofilin's severing activity is tightly regulated through multiple mechanisms, including regulation of cofilin serine phosphorylation by Rho GTPases. However, it is not known which Rho GTPase is involved in regulating cofilin's phosphorylation status at invadopodia. Results: We show here, for the first time, how RhoC activation is controlled at invadopodia and how this activation regulates cofilin phosphorylation to control cofilin's generation of actin-free barbed ends. Live-cell imaging of fluorescent RhoC biosensor reveals that RhoC activity is spatially confined to areas surrounding invadopodia. This spatiotemporal restriction of RhoC activity is controlled by "spatially distinct regulatory elements" that confine RhoC activation within this compartment. p190RhoGEF localizes around invadopodia to activate RhoC, whereas p190RhoGAP localizes inside invadopodia to deactivate the GTPase within the structure. RhoC activation enhances cofilin phosphorylation outside invadopodia. Conclusion: These results show how RhoC activity is spatially regulated at invadopodia by p190RhoGEF and p190RhoGAP. RhoC activation in areas surrounding invadopodia restricts cofilin activity to within the invadopodium core, resulting in a focused invadopodial protrusion. This mechanism likely enhances tumor cell invasion during metastasis.

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