BPGAP1 and Pin1 co‐regulate Rho, Erk and cortactin signaling in cell dynamics

Abstract

Rho small GTPases are molecular switches that regulate actin and microtubule cytoskeleton networks during cellular morphogenesis, motility, invasion and proliferation. Although these processes are also under the control of MAPK/Erk pathway and cortactin (a cortical actin‐binding protein that facilitates actin branching and polymerisation), it is unclear where and how the signaling of Rho, Erk and cortactin converge and are co‐regulated inside the cells. We recently identified BPGAP1 as a potent multi‐domain Rho GTPase‐activating protein (GAP) that not only biochemically acting to inhibit RhoA activity via its RhoGAP domain, it also promotes Erk activity and cell motility via its BNIP‐2 and Cdc42GAP Homology domain and the Proline‐rich Region (PRR). We earlier showed that PRR targets cortactin and endophilin towards cell protrusions and for EGF receptor endocytosis, respectively; both by involving their SH3 domains specifically recognizing the prolines 184 and 186 of the 182‐PRPPLP‐189 moiety. Interestingly, part of the PRR, 186‐PPLP‐189, which subtly overlaps with the cortactin‐binding site, is also a prime target of the WW domain of peptidyl‐prolyl cis/trans isomerase Pin1. Consequently, binding of Pin1 to BPGAP1 enhances its RhoGAP activity but it suppresses BPGAP1‐induced acute Erk activation and cell motility. These results raise the question on whether Pin1 could also affect the function of BPGAP1 with cortactin and whether this effect, if any, is linked to or distinct from Erk regulation. Here, we showed that Pin1 overexpression could enhance the binding of cortactin to BPGAP1. Consistently, such binding is significantly reduced in Pin1 knockdown cells. Furthermore, Pin1 overexpression also modulates the dynamic disposition of BPGAP1 and its impacts on cellular morphogenesis. How such process would involve BPGAP1 and Pin1 co‐regulating the activity of cortactin, in relation to its reduced acute Erk but enhanced RhoGAP activity in both space and time, is now being investigated.