Mechanistic insight into the microtubule and actin cytoskeleton coupling through dynein-dependent RhoGEF inhibition |
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Authors: | Meiri David Marshall Christopher B Greeve Melissa A Kim Bryan Balan Marc Suarez Fernando Bakal Chris Wu Chuanjin Larose Jose Fine Noah Ikura Mitsuhiko Rottapel Robert |
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Affiliation: | Ontario Cancer Institute and the Campbell Family Cancer Research Institute, 101 College Street, Room 8-703 Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada. |
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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. |
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