Arhgef6 (alpha‐PIX) cytoskeletal regulator signals to GTPases and Cofilin to couple T cell migration speed and persistence

• Published in: Journal of leukocyte biology Vol. 110; no. 5; pp. 839 - 852
• Main Authors: Mamula, Dejan, Korthals, Mark, Hradsky, Johannes, Gottfried, Anna, Fischer, Klaus‐Dieter, Tedford, Kerry
• Format: Journal Article
• Language: English
• Published: United States 01.11.2021
• Subjects: Cofilin; GTPases; lamellipodia; Medicin och hälsovetenskap; migration; RhoGEF; Cofilin; lamellipodia; migration; GTPases; RhoGEF
• ISSN: 0741-5400; 1938-3673; 1938-3673
• DOI: 10.1002/JLB.1A1219-719R

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; αPIX; 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−/− T cells, expression of Arhgef7 (beta‐PIX; βPIX; 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−/− 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−/− 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. Graphical Arhgef6 (alpha‐PIX) inhibits signaling to GTPases and Cofilin to restrain lamellipodia formation, cell turning, and cell migration speed.