FIGURE 8.

A proposed model for GIT1/eNOS signaling in sinusoidal endothelial cells. In sinusoidal endothelial cells, ET-1 activates its cognate G-protein-coupled receptor (ET_B receptor (ET_B R) and causes Gα and Gβγ activation and dissociation (see also Ref. 32). The mechanism of Src activation is currently unknown but may occur through ET_B receptor-mediated β-arrestin recruitment of Src (54). Activated Src phosphorylates GIT1 at Tyr²⁹³ and Tyr⁵⁵⁴ and perhaps also eNOS at Tyr⁸³ to partially activate it (41, 42). Phosphorylated GIT1 then associates with eNOS to facilitate its activating phosphorylation at Ser¹¹⁷⁷ by Akt. Receptor-activated Gβγ simultaneously stimulates Akt (at Ser⁴⁷³) activation through phosphatidylinositol (PI) 3-kinase (32), and this activation may be amplified by other signaling pathways (55). Thus, both Src and Akt kinases are crucial in the resultant phosphorylation-enhanced association of GIT1 and eNOS and in stimulating eNOS activity and NO production. dnAkt, dominant negative Akt.