{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T12:56:09Z","timestamp":1762520169592},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":720,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T00:00:00Z","timestamp":1612224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T00:00:00Z","timestamp":1612224000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,10,25]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Immunity is governed by successful T cell migration, optimized to enable a T cell to fully scan its environment without wasted movement by balancing speed and turning. Here we report that the Arhgef6 RhoGEF (aka alpha-PIX; \u03b1PIX; Cool-2), an activator of small GTPases, is required to restrain cell migration speed and cell turning during spontaneous migration on 2D surfaces. In Arhgef6\u2212\/\u2212 T cells, expression of Arhgef7 (beta-PIX; \u03b2PIX; Cool-1), a homolog of Arhgef6, was increased and correlated with defective activation and localization of Rac1 and CDC42 GTPases, respectively. Downstream of Arhgef6, PAK2 (p21-activated kinase 2) and LIMK1 phosphorylation was reduced, leading to increased activation of Cofilin, the actin-severing factor. Consistent with defects in these signaling pathways, Arhgef6\u2212\/\u2212 T cells displayed abnormal bilobed lamellipodia and migrated faster, turned more, and arrested less than wild-type (WT) T cells. Using pharmacologic inhibition of LIMK1 (LIM domain kinase 1) to induce Cofilin activation in WT T cells, we observed increased migration speed but not increased cell turning. In contrast, inhibition of Cdc42 increased cell turning but not speed. These results suggested that the increased speed of the Arhgef6\u2212\/\u2212 T cells is due to hyperactive Cofilin while the increased turning may be due to abnormal GTPase activation and recruitment. Together, these findings reveal that Arhgef6 acts as a repressor of T cell speed and turning by limiting actin polymerization and lamellipodia formation.<\/jats:p>","DOI":"10.1002\/jlb.1a1219-719r","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T04:25:59Z","timestamp":1612412759000},"page":"839-852","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Arhgef6 (alpha-PIX) cytoskeletal regulator signals to GTPases and Cofilin to couple T cell migration speed and persistence"],"prefix":"10.1093","volume":"110","author":[{"given":"Dejan","family":"Mamula","sequence":"first","affiliation":[{"name":"Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg , Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Korthals","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg , Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Hradsky","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg , Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Gottfried","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg , Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus-Dieter","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg , Magdeburg, Germany"},{"name":"Center for Cellular Imaging and Innovative Disease Models, Medical Faculty, Otto-von-Guericke University Magdeburg , Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerry","family":"Tedford","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg , Magdeburg, Germany"},{"name":"Center for Cellular Imaging and Innovative Disease Models, Medical Faculty, Otto-von-Guericke University Magdeburg , Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,2,2]]},"reference":[{"key":"2023032108464606200_","doi-asserted-by":"crossref","first-page":"586","DOI":"10.3389\/fimmu.2015.00586","article-title":"Lymphocyte migration: an action movie starring the actin and associated actors","volume":"6","author":"Dupre","year":"2015","journal-title":"Front Immunol"},{"key":"2023032108464606200_","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ceb.2016.03.025","article-title":"Multiple mechanisms of 3D migration: the origins of plasticity","volume":"42","author":"Petrie","year":"2016","journal-title":"Curr Opin cell Biol"},{"key":"2023032108464606200_","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrm3861","article-title":"Steering cell migration: lamellipodium dynamics and the regulation of directional persistence","volume":"15","author":"Krause","year":"2014","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2023032108464606200_","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/nri.2015.16","article-title":"T cell migration, search strategies and mechanisms","volume":"16","author":"Krummel","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"2023032108464606200_","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a003384","article-title":"Symmetry breaking in the life cycle of the budding yeast","volume":"1","author":"Slaughter","year":"2009","journal-title":"Cold Spring Harbor Perspect Biol"},{"key":"2023032108464606200_","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1016\/S0021-9258(17)41953-3","article-title":"Control of the yeast bud-site assembly GTPase Cdc42. 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