Rac2 Specificity in Macrophage Integrin Signaling: Potential role for Syk kinase

Herein we report that, despite the similarity of Rac2 to Racl (92% amino acid identity), macrophages derived from Rac2-/- mice, which continue to express Rac1, display a marked defect in α_vβ ₃/α_vβ₅ and α ₄β₁ integrin-directed migration measured on vitronectin and fibronectin fragments (FN-H296), respectively. In contrast, mouse embryo fibroblasts derived from the Rac2 knockout mice utilize Rac1 for migration via α_vβ₃/α_vβ ₅ and α₄β₁. The genetic reconstitution of bone marrow-derived macrophages (BMMθ) with Rac2 restores the integrin-dependent migration of Rac2-deficient macrophages on vitronectin (VN) and FN-H296. The levels of GTP-Rac2 generated upon specific integrin engagement in wild type macrophages parallels the phenotypic defect observed in Rac2-deficient macrophages; i.e. FN-H296, α ₄β₁ > VN, α_vβ ₃/α_vβ₅ > FN-CH271, α ₅β₁ > intact FN. In a COS7 cell system, the expression of Syk kinase alone is sufficient to convert the α ₄β₁ migration response to Rac2 dependence. Therefore, we present the first evidence that the α₄β₁ receptor in blood cells has evolved a Syk-Rac2 signaling axis to transmit signals required for integrin-directed migration suggesting that Syk kinase in part encodes myeloid Rac2 specificity in vivo.