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Hic-5 regulates Src-induced invadopodia rosette formation and organization

Fibroblasts transformed by the proto-oncogene Src form individual invadopodia that can spontaneously self-organize into large matrix-degrading superstructures called rosettes. However, the mechanisms by which the invadopodia can spatiotemporally reorganize their architecture is not well understood....

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Detalles Bibliográficos
Autores principales: Gulvady, Anushree C., Forsythe, Ian J., Turner, Christopher E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724605/
https://www.ncbi.nlm.nih.gov/pubmed/30893012
http://dx.doi.org/10.1091/mbc.E18-10-0629
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author Gulvady, Anushree C.
Forsythe, Ian J.
Turner, Christopher E.
author_facet Gulvady, Anushree C.
Forsythe, Ian J.
Turner, Christopher E.
author_sort Gulvady, Anushree C.
collection PubMed
description Fibroblasts transformed by the proto-oncogene Src form individual invadopodia that can spontaneously self-organize into large matrix-degrading superstructures called rosettes. However, the mechanisms by which the invadopodia can spatiotemporally reorganize their architecture is not well understood. Here, we show that Hic-5, a close relative of the scaffold protein paxillin, is essential for the formation and organization of rosettes in active Src-transfected NIH3T3 fibroblasts and cancer-associated fibroblasts. Live cell imaging, combined with domain-mapping analysis of Hic-5, identified critical motifs as well as phosphorylation sites that are required for the formation and dynamics of rosettes. Using pharmacological inhibition and mutant expression, we show that FAK kinase activity, along with its proximity to and potential interaction with the LD2,3 motifs of Hic-5, is necessary for rosette formation. Invadopodia dynamics and their coalescence into rosettes were also dependent on Rac1, formin, and myosin II activity. Superresolution microscopy revealed the presence of formin FHOD1 and INF2-mediated unbranched radial F-actin fibers emanating from invadopodia and rosettes, which may facilitate rosette formation. Collectively, our data highlight a novel role for Hic-5 in orchestrating the organization of invadopodia into higher-order rosettes, which may promote the localized matrix degradation necessary for tumor cell invasion.
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spelling pubmed-67246052019-09-06 Hic-5 regulates Src-induced invadopodia rosette formation and organization Gulvady, Anushree C. Forsythe, Ian J. Turner, Christopher E. Mol Biol Cell Articles Fibroblasts transformed by the proto-oncogene Src form individual invadopodia that can spontaneously self-organize into large matrix-degrading superstructures called rosettes. However, the mechanisms by which the invadopodia can spatiotemporally reorganize their architecture is not well understood. Here, we show that Hic-5, a close relative of the scaffold protein paxillin, is essential for the formation and organization of rosettes in active Src-transfected NIH3T3 fibroblasts and cancer-associated fibroblasts. Live cell imaging, combined with domain-mapping analysis of Hic-5, identified critical motifs as well as phosphorylation sites that are required for the formation and dynamics of rosettes. Using pharmacological inhibition and mutant expression, we show that FAK kinase activity, along with its proximity to and potential interaction with the LD2,3 motifs of Hic-5, is necessary for rosette formation. Invadopodia dynamics and their coalescence into rosettes were also dependent on Rac1, formin, and myosin II activity. Superresolution microscopy revealed the presence of formin FHOD1 and INF2-mediated unbranched radial F-actin fibers emanating from invadopodia and rosettes, which may facilitate rosette formation. Collectively, our data highlight a novel role for Hic-5 in orchestrating the organization of invadopodia into higher-order rosettes, which may promote the localized matrix degradation necessary for tumor cell invasion. The American Society for Cell Biology 2019-05-15 /pmc/articles/PMC6724605/ /pubmed/30893012 http://dx.doi.org/10.1091/mbc.E18-10-0629 Text en © 2019 Gulvady et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Gulvady, Anushree C.
Forsythe, Ian J.
Turner, Christopher E.
Hic-5 regulates Src-induced invadopodia rosette formation and organization
title Hic-5 regulates Src-induced invadopodia rosette formation and organization
title_full Hic-5 regulates Src-induced invadopodia rosette formation and organization
title_fullStr Hic-5 regulates Src-induced invadopodia rosette formation and organization
title_full_unstemmed Hic-5 regulates Src-induced invadopodia rosette formation and organization
title_short Hic-5 regulates Src-induced invadopodia rosette formation and organization
title_sort hic-5 regulates src-induced invadopodia rosette formation and organization
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724605/
https://www.ncbi.nlm.nih.gov/pubmed/30893012
http://dx.doi.org/10.1091/mbc.E18-10-0629
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