Mechanistic Insight into the Microtubule and Actin Cytoskeleton Coupling through Dynein-Dependent RhoGEF Inhibition
Actin-based stress fiber formation is coupled to microtubule depolymerization through the local activation of RhoA. While the RhoGEF Lfc has been implicated in this cytoskeleton coupling process, it has remained elusive how Lfc is recruited to microtubules and how microtubule recruitment moderates L...
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| Veröffentlicht in: | Molecular cell 2012-03, Vol.45 (5), p.642-655 |
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| creator | Meiri, David Marshall, Christopher B. Greeve, Melissa A. Kim, Bryan Balan, Marc Suarez, Fernando Wu, Chuanjin LaRose, Jose Fine, Noah Ikura, Mitsuhiko Rottapel, Robert |
| description | Actin-based stress fiber formation is coupled to microtubule depolymerization through the local activation of RhoA. While the RhoGEF Lfc has been implicated in this cytoskeleton coupling process, it has remained elusive how Lfc is recruited to microtubules and how microtubule recruitment moderates Lfc activity. Here, we demonstrate that the dynein light chain protein Tctex-1 is required for localization of Lfc to microtubules. Lfc residues 139–161 interact with Tctex-1 at a site distinct from the cleft that binds dynein intermediate chain. An NMR-based GEF assay revealed that interaction with Tctex-1 represses Lfc nucleotide exchange activity in an indirect manner that requires both polymerized microtubules and phosphorylation of S885 by PKA. We show that inhibition of Lfc by Tctex-1 is dynein dependent. These studies demonstrate a pivotal role of Tctex-1 as a negative regulator of actin filament organization through its control of Lfc in the crosstalk between microtubule and actin cytoskeletons.
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► Tctex-1 binds directly to RhoGEF Lfc and recruits it to the microtubule array ► Tctex-1-mediated inhibition of Lfc requires polymerized microtubules ► The dynein light chain Tctex-1 expression is essential for proper actin stress fiber organization ► Tctex-1 is required for mediating the crosstalk between microtubules and actin |
| doi_str_mv | 10.1016/j.molcel.2012.01.027 |
| format | Article |
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[Display omitted]
► Tctex-1 binds directly to RhoGEF Lfc and recruits it to the microtubule array ► Tctex-1-mediated inhibition of Lfc requires polymerized microtubules ► The dynein light chain Tctex-1 expression is essential for proper actin stress fiber organization ► Tctex-1 is required for mediating the crosstalk between microtubules and actin</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2012.01.027</identifier><identifier>PMID: 22405273</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>actin ; Actin Cytoskeleton - metabolism ; Actin Cytoskeleton - physiology ; Actin Cytoskeleton - ultrastructure ; Animals ; cAMP-dependent protein kinase ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Cyclic AMP-Dependent Protein Kinases - physiology ; dynein ATPase ; Dyneins - metabolism ; Dyneins - physiology ; Embryo, Mammalian - metabolism ; Embryo, Mammalian - ultrastructure ; Fibroblasts - metabolism ; Guanine Nucleotide Exchange Factors - antagonists & inhibitors ; Guanine Nucleotide Exchange Factors - metabolism ; Guanine Nucleotide Exchange Factors - physiology ; Mice ; microfilaments ; microtubules ; Microtubules - metabolism ; Microtubules - physiology ; Microtubules - ultrastructure ; Phosphorylation ; polymerization ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins - physiology ; Rho Guanine Nucleotide Exchange Factors</subject><ispartof>Molecular cell, 2012-03, Vol.45 (5), p.642-655</ispartof><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c501t-4dc4a90b2110496349d232e4c65f26f4e3329aeaddd3bafd4876fe76fc89c8403</citedby><cites>FETCH-LOGICAL-c501t-4dc4a90b2110496349d232e4c65f26f4e3329aeaddd3bafd4876fe76fc89c8403</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1097276512001694$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22405273$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meiri, David</creatorcontrib><creatorcontrib>Marshall, Christopher B.</creatorcontrib><creatorcontrib>Greeve, Melissa A.</creatorcontrib><creatorcontrib>Kim, Bryan</creatorcontrib><creatorcontrib>Balan, Marc</creatorcontrib><creatorcontrib>Suarez, Fernando</creatorcontrib><creatorcontrib>Wu, Chuanjin</creatorcontrib><creatorcontrib>LaRose, Jose</creatorcontrib><creatorcontrib>Fine, Noah</creatorcontrib><creatorcontrib>Ikura, Mitsuhiko</creatorcontrib><creatorcontrib>Rottapel, Robert</creatorcontrib><title>Mechanistic Insight into the Microtubule and Actin Cytoskeleton Coupling through Dynein-Dependent RhoGEF Inhibition</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>Actin-based stress fiber formation is coupled to microtubule depolymerization through the local activation of RhoA. While the RhoGEF Lfc has been implicated in this cytoskeleton coupling process, it has remained elusive how Lfc is recruited to microtubules and how microtubule recruitment moderates Lfc activity. Here, we demonstrate that the dynein light chain protein Tctex-1 is required for localization of Lfc to microtubules. Lfc residues 139–161 interact with Tctex-1 at a site distinct from the cleft that binds dynein intermediate chain. An NMR-based GEF assay revealed that interaction with Tctex-1 represses Lfc nucleotide exchange activity in an indirect manner that requires both polymerized microtubules and phosphorylation of S885 by PKA. We show that inhibition of Lfc by Tctex-1 is dynein dependent. These studies demonstrate a pivotal role of Tctex-1 as a negative regulator of actin filament organization through its control of Lfc in the crosstalk between microtubule and actin cytoskeletons.
[Display omitted]
► Tctex-1 binds directly to RhoGEF Lfc and recruits it to the microtubule array ► Tctex-1-mediated inhibition of Lfc requires polymerized microtubules ► The dynein light chain Tctex-1 expression is essential for proper actin stress fiber organization ► Tctex-1 is required for mediating the crosstalk between microtubules and actin</description><subject>actin</subject><subject>Actin Cytoskeleton - metabolism</subject><subject>Actin Cytoskeleton - physiology</subject><subject>Actin Cytoskeleton - ultrastructure</subject><subject>Animals</subject><subject>cAMP-dependent protein kinase</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - physiology</subject><subject>dynein ATPase</subject><subject>Dyneins - metabolism</subject><subject>Dyneins - physiology</subject><subject>Embryo, Mammalian - metabolism</subject><subject>Embryo, Mammalian - ultrastructure</subject><subject>Fibroblasts - metabolism</subject><subject>Guanine Nucleotide Exchange Factors - antagonists & inhibitors</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Guanine Nucleotide Exchange Factors - physiology</subject><subject>Mice</subject><subject>microfilaments</subject><subject>microtubules</subject><subject>Microtubules - metabolism</subject><subject>Microtubules - physiology</subject><subject>Microtubules - ultrastructure</subject><subject>Phosphorylation</subject><subject>polymerization</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins - physiology</subject><subject>Rho Guanine Nucleotide Exchange Factors</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi0EoqXwDxDk1lPC-CMfviBV2w8qtUICerYce7LxkrWX2EHaf4-rLBw5WGNLz7zjeQh5T6GiQJtPu2ofJoNTxYCyCmgFrH1BzinIthS0ES9Pd9Y29Rl5E-MOgIq6k6_JGWMCatbycxIf0Yzau5icKe59dNsxFc6nUKQRi0dn5pCWfpmw0N4WVyY5X2yOKcSfOGEK-RGWw-T8NvNzWLZjcX306Hx5jQf0Fn0qvo3h7uY2h4-ud8kF_5a8GvQU8d2pXpCn25sfmy_lw9e7-83VQ2lqoKkU1ggtoWeUgpANF9IyzlCYph5YMwjknEmN2lrLez1Y0bXNgPmYTppOAL8gl2vuYQ6_FoxJ7V3MxibtMSxRSdZ2nAOvMylWMq8b44yDOsxur-ejoqCebaudWm2rZ9sKqMq2c9uH04Cl36P91_RXbwY-rsCgg9Lb2UX19D0nNADAGJUyE59XArOI3w5nFY1Db9C6GU1SNrj__-EPDGmdJw</recordid><startdate>20120309</startdate><enddate>20120309</enddate><creator>Meiri, David</creator><creator>Marshall, Christopher B.</creator><creator>Greeve, Melissa A.</creator><creator>Kim, Bryan</creator><creator>Balan, Marc</creator><creator>Suarez, Fernando</creator><creator>Wu, Chuanjin</creator><creator>LaRose, Jose</creator><creator>Fine, Noah</creator><creator>Ikura, Mitsuhiko</creator><creator>Rottapel, Robert</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><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></search><sort><creationdate>20120309</creationdate><title>Mechanistic Insight into the Microtubule and Actin Cytoskeleton Coupling through Dynein-Dependent RhoGEF Inhibition</title><author>Meiri, David ; Marshall, Christopher B. ; Greeve, Melissa A. ; Kim, Bryan ; Balan, Marc ; Suarez, Fernando ; Wu, Chuanjin ; LaRose, Jose ; Fine, Noah ; Ikura, Mitsuhiko ; Rottapel, Robert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c501t-4dc4a90b2110496349d232e4c65f26f4e3329aeaddd3bafd4876fe76fc89c8403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>actin</topic><topic>Actin Cytoskeleton - metabolism</topic><topic>Actin Cytoskeleton - physiology</topic><topic>Actin Cytoskeleton - ultrastructure</topic><topic>Animals</topic><topic>cAMP-dependent protein kinase</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinases - physiology</topic><topic>dynein ATPase</topic><topic>Dyneins - metabolism</topic><topic>Dyneins - physiology</topic><topic>Embryo, Mammalian - metabolism</topic><topic>Embryo, Mammalian - ultrastructure</topic><topic>Fibroblasts - metabolism</topic><topic>Guanine Nucleotide Exchange Factors - antagonists & inhibitors</topic><topic>Guanine Nucleotide Exchange Factors - metabolism</topic><topic>Guanine Nucleotide Exchange Factors - physiology</topic><topic>Mice</topic><topic>microfilaments</topic><topic>microtubules</topic><topic>Microtubules - metabolism</topic><topic>Microtubules - physiology</topic><topic>Microtubules - ultrastructure</topic><topic>Phosphorylation</topic><topic>polymerization</topic><topic>Proto-Oncogene Proteins - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins - physiology</topic><topic>Rho Guanine Nucleotide Exchange Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Meiri, David</creatorcontrib><creatorcontrib>Marshall, Christopher B.</creatorcontrib><creatorcontrib>Greeve, Melissa A.</creatorcontrib><creatorcontrib>Kim, Bryan</creatorcontrib><creatorcontrib>Balan, Marc</creatorcontrib><creatorcontrib>Suarez, Fernando</creatorcontrib><creatorcontrib>Wu, Chuanjin</creatorcontrib><creatorcontrib>LaRose, Jose</creatorcontrib><creatorcontrib>Fine, Noah</creatorcontrib><creatorcontrib>Ikura, Mitsuhiko</creatorcontrib><creatorcontrib>Rottapel, Robert</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><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><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Meiri, David</au><au>Marshall, Christopher B.</au><au>Greeve, Melissa A.</au><au>Kim, Bryan</au><au>Balan, Marc</au><au>Suarez, Fernando</au><au>Wu, Chuanjin</au><au>LaRose, Jose</au><au>Fine, Noah</au><au>Ikura, Mitsuhiko</au><au>Rottapel, Robert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanistic Insight into the Microtubule and Actin Cytoskeleton Coupling through Dynein-Dependent RhoGEF Inhibition</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2012-03-09</date><risdate>2012</risdate><volume>45</volume><issue>5</issue><spage>642</spage><epage>655</epage><pages>642-655</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Actin-based stress fiber formation is coupled to microtubule depolymerization through the local activation of RhoA. While the RhoGEF Lfc has been implicated in this cytoskeleton coupling process, it has remained elusive how Lfc is recruited to microtubules and how microtubule recruitment moderates Lfc activity. Here, we demonstrate that the dynein light chain protein Tctex-1 is required for localization of Lfc to microtubules. Lfc residues 139–161 interact with Tctex-1 at a site distinct from the cleft that binds dynein intermediate chain. An NMR-based GEF assay revealed that interaction with Tctex-1 represses Lfc nucleotide exchange activity in an indirect manner that requires both polymerized microtubules and phosphorylation of S885 by PKA. We show that inhibition of Lfc by Tctex-1 is dynein dependent. These studies demonstrate a pivotal role of Tctex-1 as a negative regulator of actin filament organization through its control of Lfc in the crosstalk between microtubule and actin cytoskeletons.
[Display omitted]
► Tctex-1 binds directly to RhoGEF Lfc and recruits it to the microtubule array ► Tctex-1-mediated inhibition of Lfc requires polymerized microtubules ► The dynein light chain Tctex-1 expression is essential for proper actin stress fiber organization ► Tctex-1 is required for mediating the crosstalk between microtubules and actin</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22405273</pmid><doi>10.1016/j.molcel.2012.01.027</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | actin Actin Cytoskeleton - metabolism Actin Cytoskeleton - physiology Actin Cytoskeleton - ultrastructure Animals cAMP-dependent protein kinase Cyclic AMP-Dependent Protein Kinases - metabolism Cyclic AMP-Dependent Protein Kinases - physiology dynein ATPase Dyneins - metabolism Dyneins - physiology Embryo, Mammalian - metabolism Embryo, Mammalian - ultrastructure Fibroblasts - metabolism Guanine Nucleotide Exchange Factors - antagonists & inhibitors Guanine Nucleotide Exchange Factors - metabolism Guanine Nucleotide Exchange Factors - physiology Mice microfilaments microtubules Microtubules - metabolism Microtubules - physiology Microtubules - ultrastructure Phosphorylation polymerization Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins - physiology Rho Guanine Nucleotide Exchange Factors |
| title | Mechanistic Insight into the Microtubule and Actin Cytoskeleton Coupling through Dynein-Dependent RhoGEF Inhibition |
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