FRMPD1

FRMPD1 is a multidomain scaffold protein that organizes G-protein regulatory complexes and Hippo-pathway signaling at the membrane and in neural circuits (PMID:18566450, PMID:31114375, PMID:36180221). Through its central conserved fragment, FRMPD1 binds the tetratricopeptide repeat (TPR) domain of the G-protein regulators AGS3 and LGN/Gpsm2: structural work shows the fragment runs antiparallel along the concave TPR channel via a shared 'E/QxEx4-5E/D/Qx1-2K/R' recognition motif, occupying a site that overlaps with mInsc, NuMA, and the LGN C-terminus, with mInsc binding at higher affinity and displacing FRMPD1 (PMID:22074847, PMID:23318951). By binding AGS3 FRMPD1 stabilizes it in the membrane fraction and tunes alpha2-adrenergic receptor–mediated cAMP signaling; this anchoring is mutually exclusive with Gαi3, so rising Gαi3 switches AGS3 from FRMPD1 to Gαi3 (PMID:18566450). In rod photoreceptors, FRMPD1 is transcribed from an alternative NRL/CRX-driven promoter and partners with Gpsm2 to support the dark-dependent return of transducin (Gαt) to outer segments and proper sensitization of rod–rod-bipolar synaptic signaling (PMID:30445545, PMID:36180221). Independently, FRMPD1 uses its PDZ domain to engage the PDZ-binding motif of WWC3, promoting LATS1 phosphorylation and cytoplasmic retention of YAP, thereby acting as a tumor suppressor that restrains lung cancer proliferation and invasion (PMID:31114375). FRMPD1 protein levels are post-translationally controlled by FBXO10, which mediates stabilizing K63-linked polyubiquitination of FRMPD1 in hepatocellular carcinoma (PMID:40699790).

1. 2008 High

   Established FRMPD1 as a membrane scaffold for AGS3 that modulates GPCR-coupled cAMP signaling, answering whether FRMPD1 has a defined role in G-protein regulation.

   Evidence Yeast two-hybrid, reciprocal Co-IP, cell fractionation and siRNA knockdown with cAMP readout in CAD neuronal cells

   PMID:18566450

   Open questions at the time

   • Physiological context in which the FRMPD1-to-Gαi3 binding switch operates was not defined
   • No structural basis for the FRMPD1-AGS3 interaction was provided
2. 2011 High

   Placed FRMPD1 within the LGN-TPR interaction network governing spindle orientation, showing its binding is mutually exclusive with mInsc, NuMA and the LGN C-terminus.

   Evidence Crystal structure of LGN-mInsc complex with structure-based mutagenesis and affinity measurements

   PMID:22074847

   Open questions at the time

   • Cellular consequence of FRMPD1 occupancy of LGN versus mInsc was not tested
   • Direct FRMPD1-LGN structure not yet resolved at this stage
3. 2013 High

   Defined the atomic mode of FRMPD1-LGN recognition, identifying a short conserved motif sufficient for TPR binding shared among LGN/Pins partners.

   Evidence 2.4 Å crystal structure of LGN-TPR–FRMPD1 with truncation and mutagenesis

   PMID:23318951

   Open questions at the time

   • Functional output of the FRMPD1-LGN complex in dividing cells not addressed
   • Regulation of competition among TPR ligands in vivo not established
4. 2019 Medium

   Identified FRMPD1 as a Hippo-pathway activator and tumor suppressor, linking its PDZ domain to WWC3, LATS1 phosphorylation and YAP retention.

   Evidence Co-IP, LATS1 phospho-immunoblotting, YAP luciferase and localization assays, gain/loss-of-function in lung cancer cells and in vivo

   PMID:31114375

   Open questions at the time

   • Single-lab study without independent replication
   • Whether scaffolding to WWC3 is direct or requires additional factors not fully resolved
5. 2019 High

   Showed cell-type-specific transcriptional control of Frmpd1 via an alternative NRL/CRX-bound promoter, explaining its expression in rod and rod-bipolar cells.

   Evidence Retinal reporter electroporation, EMSA/binding assays, and in vivo CRISPR/Cas9 deletion of NRL/CRX sites

   PMID:30445545

   Open questions at the time

   • Functional consequence of the rod-specific isoform not addressed in this study
   • Whether the same promoter operates in non-retinal tissues unknown
6. 2022 High

   Defined a retinal function for FRMPD1 through its Gpsm2 interaction in transducin trafficking and rod synaptic sensitization, connecting the scaffold to phototransduction recovery.

   Evidence Co-IP, rod-specific conditional knockout mouse, Gαt immunofluorescence, and synaptic electrophysiology

   PMID:36180221

   Open questions at the time

   • Mechanistic link between FRMPD1-Gpsm2 binding and transducin transport not resolved at molecular level
   • Whether the LGN-TPR binding motif mediates the retinal Gpsm2 interaction not tested
7. 2025 Medium

   Revealed post-translational control of FRMPD1 abundance by FBXO10-mediated K63-linked ubiquitination, identifying FRMPD1 as a stabilized downstream effector in hepatocellular carcinoma.

   Evidence Co-IP, K63-linkage-specific ubiquitination assays, and functional rescue in HCC proliferation assays

   PMID:40699790

   Open questions at the time

   • Single-lab study with limited methodological detail
   • Site(s) of K63 ubiquitination on FRMPD1 not mapped
   • Relationship between stabilized FRMPD1 and its Hippo/G-protein functions not addressed

• How FRMPD1's multiple binding modes (LGN/Gpsm2, AGS3, WWC3) are coordinated within a single cell and whether they operate in shared or distinct pathways remains unresolved.
• No integrated model linking spindle-orientation, Hippo, and phototransduction roles
• Regulatory hierarchy among competing TPR ligands in vivo undefined
• Structure of full-length FRMPD1 and its domain organization uncharacterized