| Feature | Summary for human CGRRF1 | Key evidence/citation |
|---|---|---|
| Protein identity | **CGRRF1** = cell growth regulator with RING finger domain protein 1; aliases include **CGR19** and **RNF197**. Literature on ERAD/Wnt regulation refers to the same human ER-associated RING finger protein. | (pqac-00000003, pqac-00000000) |
| Primary molecular function | Best-supported function is an **ER-resident RING-type E3 ubiquitin ligase** involved in **ER-associated degradation (ERAD)** and regulatory control of membrane protein abundance, especially the Wnt cargo receptor **Evi/WLS**. | (pqac-00000003, pqac-00000001, pqac-00000008) |
| Enzymatic activity status | CGRRF1 was reported in one screen to **lack detectable in vitro autoubiquitination activity** when tested with a promiscuous E2 (UbcH5a), but later substrate-focused work showed that CGRRF1 is required for **Evi ubiquitination and degradation**, consistent with **E2- and substrate-specific E3 activity**. | (pqac-00000000, pqac-00000008, pqac-00000002) |
| Structural features | CGRRF1 is a **single-pass membrane protein** with a predicted **transmembrane segment near aa 15-37** and a **cytosolic C3HC4 RING domain at aa 274-315**. The RING contains conserved cysteine/histidine residues required for catalytic function. | (pqac-00000002, pqac-00000000) |
| Catalytic importance of RING domain | Mutation of conserved cysteines in the CGRRF1 RING domain stabilized interaction with endogenous Evi and increased Evi steady-state levels, indicating that the **intact RING domain is required for substrate turnover**. | (pqac-00000002) |
| Subcellular localization | CGRRF1 is **partially localized to the endoplasmic reticulum** and is considered one of the **ER membrane-embedded ubiquitin ligases**. Its topology places the catalytic RING domain on the **cytosolic side** of the ER membrane. | (pqac-00000000, pqac-00000007, pqac-00000002) |
| Additional localization inference | Proximity-labeling studies of nuclear-envelope proteins identified **CGRRF1 in the emerin/LBR neighborhood**, suggesting presence in the **ER–nuclear envelope continuum** and possible access to the **inner nuclear membrane proteostasis environment**. | (pqac-00000013, pqac-00000012) |
| Known substrate: Evi/WLS | The strongest experimentally supported substrate is **Evi/WLS (GPR177)**, the Wnt cargo receptor. In the absence of Wnt ligands, Evi is ubiquitinated and degraded by ERAD, requiring **CGRRF1**. | (pqac-00000003, pqac-00000001, pqac-00000002) |
| Evidence for Evi substrate assignment | **siRNA knockdown of CGRRF1** increased Evi abundance; **TUBE pulldown** showed reduced ubiquitinated Evi after CGRRF1 knockdown; **CGRRF1 co-immunoprecipitated with Evi**. | (pqac-00000002, pqac-00000001) |
| Other candidate substrates | A proteomics study suggested that CGRRF1 may influence **lamin B receptor (LBR)** abundance, but this remains **preliminary/candidate-level evidence**, not yet a firmly established direct substrate relationship. | (pqac-00000013) |
| E2 enzyme partner(s) | The best-supported cognate E2 is **UBE2J2**, which works with CGRRF1 in Evi ubiquitination. UBE2J2 and CGRRF1 depletion produce similar stabilization of Evi and reduced Evi ubiquitination. | (pqac-00000003, pqac-00000002, pqac-00000008) |
| Interacting proteins/cofactors | Factors linked to the same Evi ERAD route include **VCP/p97** for extraction/dislocation, **Porcn** as a triage factor coupling cargo loading versus degradation, and **ERLIN2**, which links EVI/WLS to the ubiquitination machinery. | (pqac-00000003, pqac-00000004, pqac-00000001) |
| ERAD role | CGRRF1 participates in **regulatory ERAD** rather than only disposal of misfolded proteins, helping tune the abundance of a mature secretory-pathway factor (Evi/WLS) according to cellular need. | (pqac-00000003, pqac-00000001, pqac-00000006) |
| Wnt pathway role | By limiting or permitting Evi/WLS abundance, CGRRF1 indirectly regulates the **capacity for Wnt ligand secretion**. Thus, CGRRF1 functions **upstream of extracellular Wnt signaling** by controlling cargo-receptor availability in Wnt-producing cells. | (pqac-00000003, pqac-00000004, pqac-00000008) |
| Mechanistic model in Wnt-producing cells | **Without palmitoleated Wnt**, Evi is polyubiquitinated and sent to ERAD via CGRRF1/UBE2J2/VCP. **With Wnt present**, Evi is stabilized, increasing secretory capacity for Wnt export. | (pqac-00000003, pqac-00000004, pqac-00000009) |
| Ubiquitin chain context | EVI/WLS was reported to carry **K11, K48, and K63-linked ubiquitin modifications** in the broader pathway analysis; CGRRF1 is specifically implicated in the Evi ubiquitination step together with UBE2J2. | (pqac-00000001, pqac-00000002) |
| ER stress regulation | CGRRF1 transcript levels were identified as **significantly upregulated by ER stress** in a genome-wide survey of candidate ERAD E3 ligases, supporting a role in ER proteostasis. | (pqac-00000000) |
| Broader ER-E3 classification | Reviews of ERAD place CGRRF1 among the set of **ER-resident transmembrane E3 ligases** whose functions extend beyond classic quality control to regulated control of signaling and metabolic proteins. | (pqac-00000007, pqac-00000006, pqac-00000005) |
| Disease/cancer relevance | The most direct disease relevance from available evidence is indirect: **CGRRF1 mRNA is reduced in some cancers** (including **endometrial** and **colon adenocarcinomas** in TCGA-based analysis discussed by Glaeser et al.), which could contribute to elevated Evi/Wnt secretory activity. | (pqac-00000008) |
| Functional implication in cancer biology | Because Evi/WLS and Wnt secretion are frequently dysregulated in cancer, CGRRF1 is proposed as a **potential modulator of Wnt-driven malignancy**, though this remains a mechanistic inference rather than a clinically validated biomarker/target. | (pqac-00000003, pqac-00000008) |
| Current limitations of knowledge | CGRRF1 remains **poorly characterized** outside the Evi/WLS pathway: substrate scope, structural mechanism, tissue-specific roles, and disease causality are still incompletely defined. Recent ERAD reviews cite CGRRF1 mainly as an example of a specialized ER-E3 in Wnt cargo-receptor control. | (pqac-00000006, pqac-00000005) |


*Table: This table compiles the main experimentally supported features of human CGRRF1, including its identity, structure, localization, enzymatic role, pathway context, and disease relevance. It is useful as a concise evidence-based reference for functional annotation of this relatively understudied ER-associated RING finger protein.*