title: CYLD regulates RhoA activity by modulating LARG ubiquitination.
abstract: Rho family guanosine triphosphatases (GTPases), such as RhoA, Cdc42, and Rac1, play a fundamental role in various cellular processes. The activation of Rho proteins is catalyzed by guanine nucleotide-exchange factors (GEFs), which promote the exchange of GDP for GTP. The precise mechanisms regulating the activation of Rho proteins are not fully understood. Herein, we demonstrate that RhoA activity is regulated by cylindromatosis (CYLD), a deubiquitinase harboring multiple functions. In addition, we find that RhoA-mediated cytoskeletal rearrangement, chromosome separation, and cell polarization are altered in CYLD-depleted cells. Mechanistically, CYLD does not interact with RhoA; instead, it interacts with and deubiquitinates leukemia-associated RhoGEF (LARG). Our data further show that CYLD-mediated deubiquitination of LARG enhances its ability to stimulate the GDP/GTP exchange on RhoA. These data thus identify LARG as a new substrate of CYLD and provide novel insights into the regulation of RhoA activation. Our results also suggest that the LARG-RhoA signaling pathway may play a role in diverse CYLD-mediated cellular events.
authors: Tianjin Key Laboratory of Protein Science and Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors: Yunfan
authors: Y
authors: Yang
authors: Lei
authors: L
authors: Sun
authors: Tala
authors: Jinmin
authors: J
authors: Gao
authors: Dengwen
authors: D
authors: Li
authors: Jun
authors: J
authors: Zhou
authors: Min
authors: M
authors: Liu
mesh_terms: D002478:Cells, Cultured; D000074749:Deubiquitinating Enzyme CYLD; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D010957:Plasmids; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C577222:ARHGEF12 protein, human; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D020742:rhoA GTP-Binding Protein