Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition
Epithelial-mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling...
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| Veröffentlicht in: | Molecular biology of the cell 2012-10, Vol.23 (20), p.4097-4108 |
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| creator | Lee, KangAe Chen, Qike K Lui, Cecillia Cichon, Magdalena A Radisky, Derek C Nelson, Celeste M |
| description | Epithelial-mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. These results reveal a novel mechanotransduction pathway in the regulation of epithelial plasticity via EMT. |
| doi_str_mv | 10.1091/mbc.E12-02-0166 |
| format | Article |
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Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. These results reveal a novel mechanotransduction pathway in the regulation of epithelial plasticity via EMT.</description><identifier>ISSN: 1059-1524</identifier><identifier>EISSN: 1939-4586</identifier><identifier>DOI: 10.1091/mbc.E12-02-0166</identifier><identifier>PMID: 22918955</identifier><language>eng</language><publisher>United States: The American Society for Cell Biology</publisher><subject>Animals ; Biomechanical Phenomena ; Breast - metabolism ; Breast - pathology ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Membrane - metabolism ; Cell Movement ; Cellular Microenvironment ; Epithelial-Mesenchymal Transition ; Extracellular Matrix - metabolism ; Female ; Focal Adhesions - metabolism ; Humans ; Integrin beta1 - metabolism ; Matrix Metalloproteinase 3 - metabolism ; Mice ; Models, Biological ; NADPH Oxidases - metabolism ; Neuropeptides - metabolism ; Protein Binding ; Protein Transport ; rac GTP-Binding Proteins - metabolism ; rac1 GTP-Binding Protein - metabolism ; Reactive Oxygen Species</subject><ispartof>Molecular biology of the cell, 2012-10, Vol.23 (20), p.4097-4108</ispartof><rights>2012 Lee 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 ( ). 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-5e09e3f4b11ba63a5e1e9c3f60554ed765aef31791ab26bf70b077477876049e3</citedby><cites>FETCH-LOGICAL-c439t-5e09e3f4b11ba63a5e1e9c3f60554ed765aef31791ab26bf70b077477876049e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469523/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469523/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22918955$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Luo, Kunxin</contributor><creatorcontrib>Lee, KangAe</creatorcontrib><creatorcontrib>Chen, Qike K</creatorcontrib><creatorcontrib>Lui, Cecillia</creatorcontrib><creatorcontrib>Cichon, Magdalena A</creatorcontrib><creatorcontrib>Radisky, Derek C</creatorcontrib><creatorcontrib>Nelson, Celeste M</creatorcontrib><title>Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition</title><title>Molecular biology of the cell</title><addtitle>Mol Biol Cell</addtitle><description>Epithelial-mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. These results reveal a novel mechanotransduction pathway in the regulation of epithelial plasticity via EMT.</description><subject>Animals</subject><subject>Biomechanical Phenomena</subject><subject>Breast - metabolism</subject><subject>Breast - pathology</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Membrane - metabolism</subject><subject>Cell Movement</subject><subject>Cellular Microenvironment</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Extracellular Matrix - metabolism</subject><subject>Female</subject><subject>Focal Adhesions - metabolism</subject><subject>Humans</subject><subject>Integrin beta1 - metabolism</subject><subject>Matrix Metalloproteinase 3 - metabolism</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>NADPH Oxidases - metabolism</subject><subject>Neuropeptides - metabolism</subject><subject>Protein Binding</subject><subject>Protein Transport</subject><subject>rac GTP-Binding Proteins - metabolism</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>Reactive Oxygen Species</subject><issn>1059-1524</issn><issn>1939-4586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1rFEEQbUQxyerZm_TRQybpmv7avgghJkaIiYiem5remmxLz_Q6PSvZ_Pp0SAwKBVVQ77161GPsHYgjEA6Ohy4cnUHbiFpgzAu2D066RumleVlnoV0DulV77KCUX0KAUsa-Zntt62DptN5nw1ecp3jLQx42KeIYiE90s004U-HfMUDHUw6Y4h3OMY-H_Ork07cLnm_jCgtxLIWGLu0OOY4rTps4r6nKpGagQmNY7wZMfJ5wLPGB_oa96jEVevvUF-zn-dmP04vm8vrzl9OTyyYo6eZGk3Ake9UBdGgkagJyQfZGaK1oZY1G6iVYB9i1puut6IS1ytqlNUJV6oJ9fNTdbLuBVoHG6iH5zRQHnHY-Y_T_b8a49jf5j5fKON3KKvDhSWDKv7dUZj_EEiglHClviweAinKufnvBjh-hYcqlTNQ_nwHhH0LyNSRP0HpRq4ZUGe__dfeM_5uKvAf7MJBB</recordid><startdate>20121015</startdate><enddate>20121015</enddate><creator>Lee, KangAe</creator><creator>Chen, Qike K</creator><creator>Lui, Cecillia</creator><creator>Cichon, Magdalena A</creator><creator>Radisky, Derek C</creator><creator>Nelson, Celeste M</creator><general>The American Society for Cell Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20121015</creationdate><title>Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition</title><author>Lee, KangAe ; Chen, Qike K ; Lui, Cecillia ; Cichon, Magdalena A ; Radisky, Derek C ; Nelson, Celeste M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-5e09e3f4b11ba63a5e1e9c3f60554ed765aef31791ab26bf70b077477876049e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Biomechanical Phenomena</topic><topic>Breast - metabolism</topic><topic>Breast - pathology</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Membrane - metabolism</topic><topic>Cell Movement</topic><topic>Cellular Microenvironment</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Extracellular Matrix - metabolism</topic><topic>Female</topic><topic>Focal Adhesions - metabolism</topic><topic>Humans</topic><topic>Integrin beta1 - metabolism</topic><topic>Matrix Metalloproteinase 3 - metabolism</topic><topic>Mice</topic><topic>Models, Biological</topic><topic>NADPH Oxidases - metabolism</topic><topic>Neuropeptides - metabolism</topic><topic>Protein Binding</topic><topic>Protein Transport</topic><topic>rac GTP-Binding Proteins - metabolism</topic><topic>rac1 GTP-Binding Protein - metabolism</topic><topic>Reactive Oxygen Species</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, KangAe</creatorcontrib><creatorcontrib>Chen, Qike K</creatorcontrib><creatorcontrib>Lui, Cecillia</creatorcontrib><creatorcontrib>Cichon, Magdalena A</creatorcontrib><creatorcontrib>Radisky, Derek C</creatorcontrib><creatorcontrib>Nelson, Celeste M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular biology of the cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, KangAe</au><au>Chen, Qike K</au><au>Lui, Cecillia</au><au>Cichon, Magdalena A</au><au>Radisky, Derek C</au><au>Nelson, Celeste M</au><au>Luo, Kunxin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition</atitle><jtitle>Molecular biology of the cell</jtitle><addtitle>Mol Biol Cell</addtitle><date>2012-10-15</date><risdate>2012</risdate><volume>23</volume><issue>20</issue><spage>4097</spage><epage>4108</epage><pages>4097-4108</pages><issn>1059-1524</issn><eissn>1939-4586</eissn><abstract>Epithelial-mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. 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| subjects | Animals Biomechanical Phenomena Breast - metabolism Breast - pathology Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Membrane - metabolism Cell Movement Cellular Microenvironment Epithelial-Mesenchymal Transition Extracellular Matrix - metabolism Female Focal Adhesions - metabolism Humans Integrin beta1 - metabolism Matrix Metalloproteinase 3 - metabolism Mice Models, Biological NADPH Oxidases - metabolism Neuropeptides - metabolism Protein Binding Protein Transport rac GTP-Binding Proteins - metabolism rac1 GTP-Binding Protein - metabolism Reactive Oxygen Species |
| title | Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition |
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