Figure 8: GIV enhances profibrogenic and inhibits antifibrogenic signalling pathways in HSCs.

Ligand stimulation of diverse classes of fibrogenic receptors (top) converges upon GIV either via direct interaction (solid arrow) or via unknown mechanism (interrupted arrow) to enhance PI3K-Akt signalling (1) and activate trimeric Gαi (2). GIV-dependent activation of Akt elicits several non-transcriptional responses (3) that lead to activation of HSCs. The GIV-PI3K-Akt pathway also modulates two distinct transcriptional programmes—(i) potentiation of the profibrotic TGFβ-SMAD pathway by increasing phosphorylation of SMAD 2/3 (4) and its translocation into the nucleus (5), and thereby enhancing proliferation and transcription of collagen and α-SMA (6); (ii) inhibition of the transcription factor FoxO1 by phosphorylation (7) and by triggering its translocation outside the nucleus (8), thereby antagonizing the antifibrotic programme (9) that FoxO1 maintains in physiology. Activation of Gi by GIV’s GEF function (2) inhibits the production of cAMP (10), a major antifibrotic pathway in HSCs by virtue of its ability to inhibit HSC migration and proliferation (11). The cAMP-PKA pathway is also known to inhibit fibrosis at a transcriptional level by phosphorylating CREB (12) that translocates to the nucleus and inhibits transcription of collagen and α-SMA (13). Profibrogenic pathways=blue; antifibrogenic=red.