APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling complex

A number of signaling proteins have been demonstrated to interact with follicle stimulating hormone (FSH) receptor (FSHR), including APPL1, 14-3-3τ and Akt2. To further define the repertoire of proteins involved in FSH-induced signal transduction, several signaling and adapter proteins were examined for the ability to associate with FSHR. This report shows that, in addition to APPL1, FSHR interacts with FOXO1a and APPL2. Moreover, APPL1 and APPL2 associate with one another via the N-terminus of APPL1, presumably via the Bin-Amphiphysin-Rvs (BAR) domain. The interactions between FSHR and APPL2 and between FSHR and FOXO1a evidently are distinct since FOXO1a does not associate with either APPL1 or with APPL2. Though APPL1 and APPL2 show some similarity in primary sequence, APPL1 associates with Akt2, whereas APPL2 does not. This is the first documented difference in function between APPL1 and APPL2. These results suggest that FSHR, APPL1, APPL2, Akt2 and FOXO1a are organized into distinct scaffolding networks in the cell. Accordingly, the spatial organization of signaling and adapter proteins with FSHR likely facilitates and finely regulates the signal transduction induced by FSH.