p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38γ motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metast...
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| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_00085472_v71_n20_p6338_Rosenthal |
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todo:paper_00085472_v71_n20_p6338_Rosenthal2023-10-03T14:06:12Z p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior Rosenthal, D.T. Iyer, H. Escudero, S. Bao, L. Wu, Z. Ventura, A.C. Kleer, C.G. Arruda, E.M. Garikipati, K. Merajver, S.D. actin mitogen activated protein kinase p38 protein serine threonine kinase Rho guanine nucleotide binding protein article breast cancer cancer cell cancer growth cancer survival cell motility cell shape controlled study cytoskeleton finite element analysis human human cell immunoprecipitation lymph node metastasis metastasis priority journal protein analysis protein expression protein phosphorylation ubiquitination Western blotting Animals Breast Neoplasms Cell Movement Computer Simulation Cytoskeleton Female Gene Expression Regulation, Neoplastic Humans Lymphatic Metastasis Mice Mitogen-Activated Protein Kinase 12 Models, Biological Neoplasm Invasiveness rho GTP-Binding Proteins Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38γ motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target. ©2011 AACR. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00085472_v71_n20_p6338_Rosenthal |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
actin mitogen activated protein kinase p38 protein serine threonine kinase Rho guanine nucleotide binding protein article breast cancer cancer cell cancer growth cancer survival cell motility cell shape controlled study cytoskeleton finite element analysis human human cell immunoprecipitation lymph node metastasis metastasis priority journal protein analysis protein expression protein phosphorylation ubiquitination Western blotting Animals Breast Neoplasms Cell Movement Computer Simulation Cytoskeleton Female Gene Expression Regulation, Neoplastic Humans Lymphatic Metastasis Mice Mitogen-Activated Protein Kinase 12 Models, Biological Neoplasm Invasiveness rho GTP-Binding Proteins |
| spellingShingle |
actin mitogen activated protein kinase p38 protein serine threonine kinase Rho guanine nucleotide binding protein article breast cancer cancer cell cancer growth cancer survival cell motility cell shape controlled study cytoskeleton finite element analysis human human cell immunoprecipitation lymph node metastasis metastasis priority journal protein analysis protein expression protein phosphorylation ubiquitination Western blotting Animals Breast Neoplasms Cell Movement Computer Simulation Cytoskeleton Female Gene Expression Regulation, Neoplastic Humans Lymphatic Metastasis Mice Mitogen-Activated Protein Kinase 12 Models, Biological Neoplasm Invasiveness rho GTP-Binding Proteins Rosenthal, D.T. Iyer, H. Escudero, S. Bao, L. Wu, Z. Ventura, A.C. Kleer, C.G. Arruda, E.M. Garikipati, K. Merajver, S.D. p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior |
| topic_facet |
actin mitogen activated protein kinase p38 protein serine threonine kinase Rho guanine nucleotide binding protein article breast cancer cancer cell cancer growth cancer survival cell motility cell shape controlled study cytoskeleton finite element analysis human human cell immunoprecipitation lymph node metastasis metastasis priority journal protein analysis protein expression protein phosphorylation ubiquitination Western blotting Animals Breast Neoplasms Cell Movement Computer Simulation Cytoskeleton Female Gene Expression Regulation, Neoplastic Humans Lymphatic Metastasis Mice Mitogen-Activated Protein Kinase 12 Models, Biological Neoplasm Invasiveness rho GTP-Binding Proteins |
| description |
Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38γ motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target. ©2011 AACR. |
| format |
JOUR |
| author |
Rosenthal, D.T. Iyer, H. Escudero, S. Bao, L. Wu, Z. Ventura, A.C. Kleer, C.G. Arruda, E.M. Garikipati, K. Merajver, S.D. |
| author_facet |
Rosenthal, D.T. Iyer, H. Escudero, S. Bao, L. Wu, Z. Ventura, A.C. Kleer, C.G. Arruda, E.M. Garikipati, K. Merajver, S.D. |
| author_sort |
Rosenthal, D.T. |
| title |
p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior |
| title_short |
p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior |
| title_full |
p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior |
| title_fullStr |
p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior |
| title_full_unstemmed |
p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior |
| title_sort |
p38γ promotes breast cancer cell motility and metastasis through regulation of rhoc gtpase, cytoskeletal architecture, and a novel leading edge behavior |
| url |
http://hdl.handle.net/20.500.12110/paper_00085472_v71_n20_p6338_Rosenthal |
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