Fig. 1

Overview of PHR protein signaling in worms, flies and vertebrates. PHR proteins function as intracellular signaling hubs that regulate numerous signaling pathways to control neuronal development. Molecules that bind to the PHR proteins are shown adjacent to (a) RPM-1, (b) Highwire, and (c) Phr1. For example, RPM-1 binds to ANC-1/Nesprin, GLO-4, PPM-2, RAE-1, and the FSN-1 complex. Direct protein interactions with RPM-1 are shown in direct contact and protein interactions that could be direct or indirect are shown with open space. The location of binding on PHR proteins is arbitrarily assigned for all proteins except RAE-1, the FSN-1/Fbxo45 complex, Myc, adenylate cyclase, Rheb, and Ran. GLO-4 binds to a large N-terminal portion of RPM-1, but this interaction has not been more extensively mapped. To date, FBD1 has only been tested for binding to FSN-1. Our diagram proposes that FBD1 is potentially the site where Skp anchors FSN-1/Fbxo45 on the PHR proteins. However, it is also possible FBD1 binds directly to FSN-1, and another site in the PHR proteins binds to Skp proteins. Note, several signaling pathways that function downstream of the PHR proteins have not been explored across model systems. FSN-1/Fbxo45, DLK-1/Dlk, JNK, p38 MAPK, and RAE-1 are conserved signaling mechanisms that mediate PHR protein function. Conserved protein domains in the PHR proteins are highlighted: RCC1-like GEF domain (RLD), PHR family specific domains (PHR), RAE-1 binding domain (RBD), FSN-1 binding domain 1 (FBD1), Myc binding domain (MBD) and RING-H2 ubiquitin ligase domain (RING)