TTC7B

TTC7B is a scaffold subunit of the plasma membrane phosphatidylinositol 4-kinase (PI4KA) complex, where it bridges the catalytic kinase PI4KA, FAM126A, and the membrane anchor EFR3 to drive phosphatidylinositol 4-phosphate (PI4P) production (PMID:34663815, PMID:39705356, PMID:38746453). Cryo-EM and HDX-MS analyses show that the EFR3A C-terminus undergoes a disorder-to-order transition upon binding and makes direct contacts with both TTC7B and FAM126A, and that complex-disrupting mutations in TTC7B reduce PI4KA recruitment to the plasma membrane (PMID:39705356, PMID:38746453); the EFR3A-TTC7B-FAM126A combination binds with ~10-fold higher affinity than most other EFR3-TTC7-FAM126 pairings, and sterically blocking the EFR3-TTC7B interface with a selective nanobody decreases PI4KA membrane recruitment and PI4P production (PMID:41197736, PMID:41473329). Assembly and activity of the complex are dynamically regulated: calcineurin dephosphorylates FAM126A to promote PI4KA activity and PI4P production during Gq-coupled GPCR signaling, while EFR3B phosphorylation markedly weakens binding to TTC7-FAM126 (PMID:34663815, PMID:41197736, PMID:41473329). Through its PI4KA-linked role, TTC7B modulates AKT signaling with context-dependent outcomes in cancer: it activates a PI4KA-AKT1-RXRA-FTO axis that lowers RNA m6A and suppresses colon cancer proliferation (PMID:39897037), yet activates AKT-dependent JKAMP induction that promotes head and neck cancer migration and invasion (PMID:41392613). TTC7B protein levels are controlled by TRIM21-mediated ubiquitination, which is antagonized by GIPC1, and stabilized TTC7B suppresses mTOR/NF-κB signaling in colorectal cancer (PMID:41522336). TTC7B also binds Chikungunya virus nsP2 and contributes to nsP2-induced host cell shutoff (PMID:22258240).

1. 2012 Medium

   Established a first cellular role for TTC7B by identifying it as a host interactor of a viral protein, linking it to virus-induced host shutoff before its core biochemistry was known.

   Evidence High-throughput yeast two-hybrid with protein complementation assay validation and siRNA knockdown luciferase reporter assays for Chikungunya nsP2

   PMID:22258240

   Open questions at the time

   • Mechanism downstream of the TTC7B-nsP2 interaction not resolved
   • No connection to PI4KA biology made at this stage
   • Single-study interaction without reciprocal endogenous validation
2. 2021 High

   Placed TTC7B within a defined plasma membrane PI4KA complex and showed the complex is dynamically regulated, answering how PI4P production is controlled during GPCR signaling.

   Evidence HDX-MS, Co-IP, calcineurin substrate identification, PI4P production assay, and palmitoylation experiments

   PMID:34663815

   Open questions at the time

   • TTC7B's own contribution to catalysis vs. scaffolding not separated
   • Direct TTC7B contacts within the complex not mapped at residue level
3. 2024 High

   Resolved the structural basis for complex assembly, showing how the EFR3A C-terminus engages TTC7B and FAM126A to recruit PI4KA to the membrane.

   Evidence Cryo-EM structure of the EFR3A C-terminus bound to PI4KA-TTC7B-FAM126A with HDX-MS and mutational plasma-membrane recruitment assays

   PMID:38746453 PMID:39705356

   Open questions at the time

   • Does not define isoform-specific differences among EFR3/TTC7/FAM126 paralogs
   • Dynamics of complex assembly in live cells not captured
4. 2025 High

   Quantified the determinants of complex specificity and demonstrated that targeting the EFR3-TTC7B interface is sufficient to inhibit PI4KA activity, defining TTC7B as a druggable node.

   Evidence Yeast-display nanobody selection, cryo-EM, HDX-MS, reconstituted lipid bilayer and cellular PI4P assays, and binding affinity measurements

   PMID:41197736 PMID:41473329

   Open questions at the time

   • Physiological consequence of high EFR3A-TTC7B-FAM126A affinity preference not tested in tissue
   • Phosphoregulation of EFR3B binding not linked to an upstream kinase
5. 2025 Medium

   Connected TTC7B's PI4KA scaffolding role to AKT-dependent transcriptional programs, but revealed opposing tumor phenotypes depending on context.

   Evidence Cancer cell lines and xenografts with TTC7B knockdown/overexpression, AKT inhibition, RXRA promoter binding, m6A quantification, FTO ablation (colon), and JKAMP epistasis with IGF-1 rescue (head and neck)

   PMID:39897037 PMID:41392613

   Open questions at the time

   • Biochemical link between PI4KA binding and AKT activation not directly reconstituted
   • Why TTC7B-AKT signaling is antiproliferative in colon but pro-invasive in head and neck cancer is unexplained
   • Single-lab functional data per cancer type
6. 2026 Medium

   Identified how TTC7B protein abundance is set, showing TRIM21-mediated ubiquitination is antagonized by GIPC1 to control downstream mTOR/NF-κB signaling.

   Evidence Ubiquitination assays, TRIM21 E3 ligase knockdown, GIPC1 manipulation, in vitro functional assays, and in vivo tumor models with GIPC1 nanoparticles plus 5-FU

   PMID:41522336

   Open questions at the time

   • Direct TRIM21-TTC7B ubiquitination site not mapped
   • Whether stability control intersects the PI4KA complex assembly is unknown
   • Single-lab study

• How TTC7B's structurally defined PI4KA-scaffolding function mechanistically produces its divergent AKT/mTOR/NF-κB signaling outputs across tissues remains unresolved.
• No direct biochemical chain linking PI4P production to AKT activation by TTC7B
• Context-dependence of pro- vs. anti-tumor effects unexplained
• Regulatory crosstalk between ubiquitination, phosphoregulation, and complex assembly not integrated