Protocadherin-7 Regulates Monocyte Migration Through Regulation of Small GTPase RhoA and Rac1

Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup within the cadherin superfamily. Pcdh7 has been shown to control osteoclast differentiation via the protein phosphatase 2A (PP2A)-glycogen synthase kinase-3β (GSK3β)-small GTPase signaling axis. As protocadherins serve multiple biological functions, a deeper understanding of Pcdh7's biological features is valuable. Using an in vitro mouse monocyte cell culture system, we demonstrate that Pcdh7 plays a role in regulating monocyte migration by modulating the small GTPases RhoA and Rac1. Pcdh7-deficient (Pcdh7) bone marrow-derived monocytes exhibited impaired migration along with the reduced activation of RhoA and Rac1. This impaired migration was rescued by transduction with constitutively active forms of RhoA and Rac1. Treatment with the PP2A-specific activator DT-061 enhanced cell migration, whereas treatment with the GSK3β-specific inhibitor AR-A014418 inhibited migration in wild-type monocytes. In contrast, treatment with DT-061 failed to restore the impaired migration in Pcdh7 monocytes. These findings suggest the involvement of PP2A and GSK3β in monocyte migration, although the forced activation of PP2A alone is insufficient to restore impaired migration in Pcdh7 monocytes. Taken together, these results indicate that Pcdh7 regulates monocyte migration through the activation of RhoA and Rac1. Given the pivotal role of cell migration in both physiological and pathological processes, our findings provide a foundation for future research into therapeutic strategies targeting Pcdh7-regulated migration.