FRMD5

FRMD5 is a FERM domain-containing scaffolding protein that controls cell adhesion and motility at junctional and adhesive contacts and that supports neuronal and epithelial developmental programs (PMID:22846708, PMID:36206744). At adherens junctions it forms a complex with p120-catenin through its C-terminal region, and its loss promotes cancer cell migration, invasion, and tumor growth, defining a tumor-suppressive role tied to cell-cell contact (PMID:22846708). It additionally couples cell-matrix and cytoskeletal control by binding directly to the integrin β5 cytoplasmic tail to promote spreading on vitronectin while interacting with ROCK1 to inhibit its activation, thereby restraining myosin light chain phosphorylation and actin stress fiber formation (PMID:25448675). Beyond adhesion, FRMD5 acts as a signaling scaffold that binds JAK2 and STAT3, enhances JAK2/STAT3 complex assembly and STAT3 phosphorylation, and thereby drives epithelial apoptosis required for vaginal lumen formation in vivo (PMID:42003911). In the nervous system FRMD5 is a neuron-expressed synaptic scaffold whose loss disrupts neuronal morphology and the distribution of synaptic proteins, and disease-associated missense variants behave as partial loss-of-function or dominant-negative alleles in a rescue-based fly model, establishing FRMD5 as a neurodevelopmental disease gene (PMID:36206744, PMID:38228891).

1. 2012 Medium

   Established the first molecular function of FRMD5 by placing it at adherens junctions in a complex with p120-catenin and linking it to suppression of tumor cell motility.

   Evidence Co-IP with C-terminal domain mapping plus siRNA knockdown with migration/invasion and in vivo tumor assays in lung cancer cells

   PMID:22846708

   Open questions at the time

   • Single lab; structural basis of the FRMD5–p120-catenin interaction undefined
   • Whether junctional localization requires the FERM domain not resolved
2. 2014 Medium

   Extended FRMD5 function from cell-cell contacts to cell-matrix adhesion and cytoskeletal control by identifying direct integrin β5 and ROCK1 binding.

   Evidence Co-IP/pulldown, siRNA knockdown, migration assays, MLC phosphorylation and actin staining

   PMID:25448675

   Open questions at the time

   • Mechanism by which FRMD5 inhibits ROCK1 activation not defined
   • Single lab; relationship between integrin and ROCK1 arms of the mechanism unresolved
3. 2018 Medium

   Positioned FRMD5 within a signaling cascade by showing its expression is regulated downstream of a Cav1/LRP6/β-catenin axis in hepatocellular carcinoma.

   Evidence Expression profiling, knockdown, constitutively active β-catenin rescue, Western blot and in vivo tumorigenesis

   PMID:30583072

   Open questions at the time

   • Whether FRMD5 is a direct transcriptional target or stabilized post-translationally not distinguished
   • Single lab; functional output of FRMD5 in this axis not mechanistically dissected
4. 2022 High

   Defined FRMD5 as a neuronal gene whose dysfunction causes disease, using orthologous rescue and variant testing to demonstrate that patient missense alleles are partial loss-of-function or dominant-negative.

   Evidence Drosophila LoF mutants, human cDNA rescue, six variant functional tests, seizure and light-response behavioral assays

   PMID:36206744

   Open questions at the time

   • Molecular function disrupted in neurons not identified at the protein level
   • Human partners mediating the neuronal role not mapped in this system
5. 2024 Medium

   Identified the cellular basis of FRMD5's neuronal role by showing knockout disrupts neuronal morphology and synaptic protein distribution relevant to ASD pathology.

   Evidence Frmd5 knockout mouse with behavioral assays, neuromorphology, and TMT quantitative synaptic proteomics

   PMID:38228891

   Open questions at the time

   • Direct synaptic binding partners of FRMD5 not established
   • Single lab; mechanistic link between altered protein distribution and behavior not defined
6. 2026 High

   Revealed a distinct signaling-scaffold function by showing FRMD5 binds JAK2 and STAT3 to promote pathway activation and epithelial apoptosis during organ morphogenesis.

   Evidence Co-IP of Frmd5 with Jak2/Stat3, Cdh16-Cre conditional KO, phospho-STAT3, apoptotic gene qPCR, vaginal morphology

   PMID:42003911

   Open questions at the time

   • Domain of FRMD5 mediating JAK2/STAT3 binding not mapped
   • Whether this scaffolding role intersects with its adhesion functions unknown

• How the FERM domain and C-terminal region of FRMD5 are partitioned across its adhesion, cytoskeletal, JAK2/STAT3, and synaptic scaffolding roles, and whether these reflect one unified biochemical activity, remains unresolved.
• No structural model of FRMD5 or its complexes
• Domain requirements for the JAK2/STAT3 and synaptic functions not mapped
• Unifying molecular activity across cell types not established