Figure 1.

Regulation of P-Rex1 activity. (A) Domain structure of P-Rex1 showing the DH-PH tandem, PDZ domains, DEP domains, and IP4P-like domain. (B) Proposed cycle of activation/deactivation of P-Rex1. In response to receptor activation, inactive P-Rex1 in the cytoplasm is recruited to the plasma membrane by direct interactions with PIP₃, Gβγ subunits and norbin. The interactions with norbin and PIP₃ occur via the PH domain, while Gβγ subunits bind directly to the DH domain. At the plasma membrane P-Rex1 GEF-activity toward Rac is stimulated by PIP₃, Gβγ and norbin, thus resulting in the release of GDP from Rac and the binding of GTP. PKA phosphorylates P-Rex1 at the plasma membrane in Ser436 located in the first DEP domain, which results in intramolecular autoinhibitory interactions between the DH-PH tandem and the first DEP domain.