FIGURE 5.

Model for PAK-dependent regulation of PREX1 phosphorylation and function by membrane receptors. PREX phosphorylation can be regulated by either RTKs or GPCRs. After RTK activation of PREX GEF activity, the Rac-dependent PAKs stimulate the phosphorylation of PREX proteins around 1–2 min after treatment with various RTK ligands. This causes a reduction in PIP₃ binding and a reduction in PIP₃-stimulated GEF activity and potentially weakens the membrane binding of PREX proteins. Downstream of certain GPCRs that are known to activate PKA, PAKs mediate the phosphorylation of PREX1 within 30 s of treatment with an agonist. PREX proteins are activated by Gβγ and PIP3 to promote GTP loading on Rac, which can then activate PAK-dependent phosphorylation of PREX1 or PREX2. Additionally, PKA is activated by Gα, and it then potentially binds to Rac-GTP to phosphorylate and activate PAKs and increase the PAK signal. This would allow for PAK-mediated phosphorylation of PREX proteins that relies on both PAK and PKA. While in this signaling complex, PKA may also phosphorylate PREX, and both PAK and PKA-mediated phosphorylation could provide negative feedback by reducing the binding of PREX to Gβγ and PIP₃. PP1α and PP2A dephosphorylation may complete the circuit and allow for PREX proteins to become activated by future stimulation of the receptor.