| Major functional role | Mechanism / complexes | Key partners | Evidence type | Key citations (with year) |
|---|---|---|---|---|
| S100A6 Ca2+-dependent binding and domain mapping | CACYBP/CacyBP-SIP is a modular adaptor with N-terminal helical hairpin, central CS/p23-like domain, and C-terminal SGS region; S100A6 binds the C-terminal SGS region in a strictly Ca2+-dependent manner. Structural mapping localized a minimal S100A6-binding segment to Ser189-Arg219, with two helices engaging the S100A6 dimer, including a novel interface-spanning mode. | S100A6 (calcyclin); SGS/C-terminal region of CACYBP | Structural (NMR/PDB), biochemical (ITC, mutagenesis), cell-based functional assays | Lee et al., 2008; S100A6/CACYBP reviews 2018, 2023 (pqac-00000004, pqac-00000012, pqac-00000008, pqac-00000029) |
| SCF-TBL1 / Siah1 / Skp1 involvement and beta-catenin degradation | CACYBP/SIP functions as a scaffold in a putative SCF-like E3 ligase (often termed SCF-TBL1), linking Siah1 and Skp1/TBL1 modules and promoting ubiquitin-proteasome degradation of non-phosphorylated beta-catenin. S100A6 binding can antagonize this anti-beta-catenin function; deletion of the S100-binding region strengthens beta-catenin loss and growth suppression. | Siah1, Skp1, TBL1, beta-catenin, S100A6 | Structural, biochemical (co-IP, proteasome inhibition), cell assays (reporters, proliferation), animal xenograft | Lee et al., 2008; Ning et al., 2012; reviews 2018, 2023 (pqac-00000012, pqac-00000013, pqac-00000014, pqac-00000009, pqac-00000015) |
| ERK1/2 (and p38/tau) phosphatase activity, regulated by phosphorylation and S100A6 | CACYBP/SIP binds ERK1/2 and lowers downstream Elk-1 phosphorylation; review evidence also supports activity toward p38 and tau. Activity is modulated by PKC phosphorylation at Ser22/Thr23 (enhancing ERK1/2 phosphatase activity), CKII phosphorylation at Thr184, and Ca2+/S100A6 binding, which can inhibit Thr184 phosphorylation and alter phosphatase output. | ERK1/2, Elk-1, p38, tau, PKC, CKII, S100A6 | Biochemical, cell-based signaling assays, review synthesis of mechanistic studies | Wasik & Filipek, 2013; Filipek & Leśniak, 2018; S100A6 reviews 2023 (pqac-00000016, pqac-00000009, pqac-00000021) |
| Cytoskeleton organization and neuronal/cell-shape functions | CACYBP/SIP binds cytoskeletal proteins and is proposed to couple microtubule and actin systems; reported roles include tubulin assembly/transport, actin polymerization, and tau association/co-localization, consistent with functions in neurite outgrowth and differentiation. | Tubulin, actin, tropomyosin, tau | Biochemical binding, cell imaging/localization, functional cell assays, review synthesis | Reviews 2018 and 2012 source synthesis; SUMO paper context 2013 (pqac-00000011, pqac-00000010, pqac-00000016) |
| Stress, nucleolar roles, localization control, and SUMOylation at K16 | CACYBP/SIP is mainly cytosolic but can relocalize to perinuclear/nuclear compartments after increased intracellular Ca2+, retinoic acid, or oxidative stress. It interacts with nucleolar protein NPM1 and contributes to nucleolar integrity/stress responses. It is SUMOylated by Ubc9 at Lys16; the SUMO-conjugated form is unusually enriched in cytoplasm, and stress can raise CACYBP/SIP levels by ~40-50% in reported systems. | Ubc9, SUMO1, NPM1, S100A6, stress pathways | Biochemical (co-IP, mutagenesis, fractionation), cell localization, stress-response assays | Wasik & Filipek, 2013; Filipek & Leśniak, 2018 (pqac-00000023, pqac-00000024, pqac-00000027, pqac-00000022, pqac-00000028) |
| 2024 pan-cancer biomarker findings | Large integrative pan-cancer analysis found broad CACYBP dysregulation and prognostic/immune associations. Dataset comprised 18,787 samples overall, including 10,080 GTEx/TCGA-profiled samples in one analysis summary; CACYBP was upregulated in 14 cancers, associated with prognosis in 13 cancers, and discriminated 15 cancers with AUC > 0.80; overall AUC was reported as 0.95 (95% CI 0.92-0.96), with some summaries noting 0.97; six paired LUAD samples provided protein-level validation. | Multi-cancer cohorts, immune infiltration metrics, TMB, MSI, LUAD validation samples | Clinical-omics / bioinformatics with limited wet-lab validation | Mo et al., 2024 (pqac-00000017, pqac-00000018, pqac-00000019, pqac-00000020) |


*Table: This table summarizes the major experimentally supported and emerging roles of human CACYBP/CacyBP-SIP, organized by mechanism, partners, evidence type, and key citations. It is useful as a compact functional annotation reference spanning core biochemistry through recent 2024 translational findings.*