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

Abstract

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; PIX; 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; PIX; 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.

Rac1: A Regulator of Cell Migration and a Potential Target for Cancer Therapy

“…The migration speed and turning of T cells need to be restrained to avoid wasted movement. A previous study revealed that Arhgef6 can control Rac1 activity to repress actin polymerization and lamellipodia formation, which limits T-cell speed and turning [ 70 ]. Cells not only extend pseudopodia ahead during migration, but also retract cell uropods.…”

Impaired migratory phenotype of CD4+ T cells in Parkinson’s disease

“…During random migration, CD4 + T cells need to optimally scan their environment to properly exert their function and this process is critically influenced by velocity and directionality 12 . The velocity and directionality of CD4 + T cells are regulated by specific molecular signaling to GTPases and cofilin 13 . Lymphocyte migration is highly dependent on the proper positioning of mitochondria at the uropod with their localized ATP production 14 – 16 .…”