| Claim/Topic | Key findings | Evidence type (review/primary/GWAS/epigenetic/database) | Species/cell context | Quantitative data | Source (author year, journal) | URL/DOI |
|---|---|---|---|---|---|---|
| Identity verification | Target literature matches **CNKSR3/CNK3** = connector enhancer of kinase suppressor of Ras 3, a CNK-family scaffold; retrieved mechanistic sources do **not** support conflation with **MAGI1** | Review synthesis | Human/mammalian renal physiology literature | None reported | Soundararajan et al. 2012, *Mol Cell Endocrinol*; Soundararajan et al. 2012, *Crit Rev Biochem Mol Biol* (pqac-00000001, pqac-00000003) | https://doi.org/10.1016/j.mce.2011.11.003 ; https://doi.org/10.3109/10409238.2012.678285 |
| Domain architecture | CNKSR3 has **SAM**, **CRIC**, and **PDZ** domains; reviews note it is smaller than other CNKs and lacks the C-terminal **PH** domain present in other family members | Review | Mammalian CNK family; renal epithelial context | No effect size | Soundararajan et al. 2012, *Mol Cell Endocrinol*; Soundararajan et al. 2012, *Crit Rev Biochem Mol Biol* (pqac-00000012, pqac-00000014, pqac-00000013) | https://doi.org/10.1016/j.mce.2011.11.003 ; https://doi.org/10.3109/10409238.2012.678285 |
| Inferred molecular role | Modular architecture supports a **scaffold/adaptor** role organizing aldosterone-responsive ENaC-regulatory machinery and modulating **Raf-1/MEK/ERK** signaling | Review/primary summary | Renal collecting duct epithelial models | No single numeric estimate | Ziera 2009; Soundararajan et al. 2012 (pqac-00000012, pqac-00000016) | https://doi.org/10.14279/depositonce-2286 ; https://doi.org/10.1016/j.mce.2011.11.003 |
| Direct MR target gene | CNKSR3 is a **direct mineralocorticoid receptor (MR) target**; promoter harbors MR-binding loci and distal GRE cluster contributing to aldosterone responsiveness | Primary + review summary | HEK293-hMR+, M1-rMR+ cells; collecting duct | MR binding at **2 promoter regions**; **3 of 4** predicted GREs in distal region contributed in mutation analysis | Ziera 2009; Soundararajan et al. 2012 (pqac-00000027, pqac-00000026, pqac-00000028) | https://doi.org/10.14279/depositonce-2286 ; https://doi.org/10.3109/10409238.2012.678285 ; https://doi.org/10.1016/j.mce.2011.11.003 |
| Aldosterone induction | Aldosterone induces CNKSR3 transcript expression downstream of MR | Primary/review summary | Distal nephron/collecting duct models | **~3-fold** increase in CNKSR3 mRNA after **1 nM aldosterone**; qPCR induction after **4 h, 10 nM aldosterone** also reported | Valinsky et al. 2019, *Vitam Horm*; Ziera 2009 (pqac-00000023, pqac-00000024) | https://doi.org/10.1016/bs.vh.2018.10.004 ; https://doi.org/10.14279/depositonce-2286 |
| Tissue/localization pattern | High expression in **connecting tubule (CNT)** and **cortical collecting duct (CCD)**, the aldosterone-sensitive nephron segments | Primary/review summary | Kidney distal nephron | No single numeric estimate | Ziera 2009; Soundararajan et al. 2012 (pqac-00000006, pqac-00000011, pqac-00000023) | https://doi.org/10.14279/depositonce-2286 ; https://doi.org/10.1016/j.mce.2011.11.003 ; https://doi.org/10.1016/bs.vh.2018.10.004 |
| ENaC regulation: necessity | CNKSR3 is required for **ENaC-mediated Na+ transport**; knockdown strongly impairs amiloride-sensitive current | Primary/review summary | Collecting duct epithelial cells / short-circuit current assays | **~80%** CNKSR3 knockdown caused **~75%** decrease in ENaC-mediated short-circuit current; shRNA silencing “almost abrogated” transport | Valinsky et al. 2019; Ziera 2009 (pqac-00000023, pqac-00000024) | https://doi.org/10.1016/bs.vh.2018.10.004 ; https://doi.org/10.14279/depositonce-2286 |
| ENaC regulation: sufficiency | CNKSR3 overexpression enhances aldosterone-dependent ENaC-mediated transepithelial Na+ transport | Primary | M1-rMR+ collecting duct model | Directional increase reported; no precise fold value in retrieved excerpts | Ziera 2009 (pqac-00000024, pqac-00000025) | https://doi.org/10.14279/depositonce-2286 |
| MAPK/ERK mechanism | CNKSR3 restrains **Raf-1/MEK/ERK** signaling; loss of CNKSR3 increases MEK1/2 and ERK1/2 phosphorylation, consistent with relief of tonic ENaC inhibition | Primary/review summary | M1-rMR+ cells; renal epithelial context | Knockdown increased phospho-MEK1/2 and phospho-ERK1/2; MEK inhibitor **U0126** markedly increased ΔISC in CNKSR3-silenced cells | Ziera 2009; Soundararajan et al. 2012; Valinsky et al. 2019 (pqac-00000025, pqac-00000012, pqac-00000023) | https://doi.org/10.14279/depositonce-2286 ; https://doi.org/10.1016/j.mce.2011.11.003 ; https://doi.org/10.1016/bs.vh.2018.10.004 |
| Interaction partners / ERC | CNKSR3 is proposed/observed in an **ENaC regulatory complex (ERC)** with **ENaC, SGK1, Raf-1, Nedd4-2** at/near the plasma membrane; GILZ may cooperate functionally, though direct inclusion was not consistently detected | Review/primary summary | Distal nephron epithelial models | No stoichiometric values | Valinsky et al. 2019; Soundararajan et al. 2012 (pqac-00000023, pqac-00000012, pqac-00000019) | https://doi.org/10.1016/bs.vh.2018.10.004 ; https://doi.org/10.1016/j.mce.2011.11.003 |
| Additional binding partners | Proteomics identified peptides from all three **PP2A** subunits as abundant CNKSR3-associated proteins, suggesting phosphoregulation-linked scaffolding | Review citing proteomics | Renal epithelial context | “Most abundant binding partners” in cited proteomics; no numeric enrichment in retrieved excerpt | Soundararajan et al. 2012 (pqac-00000028, pqac-00000012) | https://doi.org/10.1016/j.mce.2011.11.003 |
| Expert interpretation | Reviews argue CNKSR3 likely acts as a **hormone-induced scaffolding platform** that disinhibits ENaC by coordinating stimulatory and inhibitory nodes, but direct effects on ENaC surface abundance vs. channel open probability remain unresolved | Review/expert opinion | Renal physiology | No quantitative metric | Johnston et al. 2023, *Compr Physiol*; Soundararajan et al. 2012 (pqac-00000009, pqac-00000035) | https://doi.org/10.1002/cphy.c190043 ; https://doi.org/10.3109/10409238.2012.678285 |
| 2023 development | Recent renal physiology review places CNKSR3 among aldosterone-induced genes that increase Na+ transport mainly by **suppressing tonic inhibitory mechanisms** rather than directly activating transporters | Review | Kidney/aldosterone physiology | No CNKSR3-specific fold value in this review | Johnston et al. 2023, *Compr Physiol* (pqac-00000009) | https://doi.org/10.1002/cphy.c190043 |
| 2024 development: DKD genetics | A **GWAS/meta-analysis** implicated a locus near **SCAF8/CNKSR3** in diabetic kidney disease (DKD), giving human genetic support for kidney relevance | GWAS/review | Human, transethnic DKD cohorts | **rs12523822**; **OR 0.73**; **p = 1.3×10−8** in T1D+T2D DKD meta-analysis; **43% lower risk** in American Indians with **p = 5.7×10−9**; **5,226 cases / 8,510 controls**; final meta-analysis **13,736 participants** | Sandholm et al. 2024, *Front Endocrinol* (pqac-00000020, pqac-00000030, pqac-00000033) | https://doi.org/10.3389/fendo.2023.1163001 |
| 2024 development: epigenetics | Epigenetic study in Korean veterans linked significant T2D-associated CpGs to **CNKSR3**, highlighting it as a collecting-duct/aldosterone-responsive candidate in metabolic-kidney disease context | Epigenetic study | Human blood methylation/genotype analysis | Study reported **2,135 AO-related DMPs** overall; CNKSR3 named among genes with significant CpGs, but no CNKSR3-specific effect size/p-value in retrieved excerpt | Seo et al. 2024, *Front Endocrinol* (pqac-00000021, pqac-00000031) | https://doi.org/10.3389/fendo.2024.1375459 |
| Disease association aggregation | Open Targets links CNKSR3 to **pregnancy-induced hypertension** and **glomerulonephritis** via GWAS credible-set evidence; these are hypothesis-generating rather than definitive mechanistic proof | Database aggregation | Human disease genetics aggregation | Evidence size **5** for listed disease associations in retrieved output | Open Targets Platform query (2025 platform paper cited by tool) (pqac-00000032, pqac-00000000) | https://platform.opentargets.org/target/ENSG00000153721 |


*Table: This table compiles the main mechanistic, experimental, and recent human genetics evidence for human CNKSR3 (UniProt Q6P9H4). It highlights domain structure, aldosterone/MR and ENaC functions, interaction partners, and 2023–2024 disease-relevant findings with quantitative statistics where available.*