Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Nuclear localization is supported; CACYBP redistributes to the nucleus upon calcium increase and stimulation, consistent with its role in degradation of nuclear/cytoplasmic substrates. Reason: CACYBP is documented in the nucleus and cytoplasm, with calcium-dependent nuclear redistribution. Supporting Evidence: file:human/CACYBP/CACYBP-uniprot.txt it localizes in both the nucleus and cytoplasm
GO:0019005 SCF ubiquitin ligase complex	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: The Siah1-SIP-Skp1-Ebi complex CACYBP participates in is a SIAH1 RING-finger E3 ligase, not a canonical SCF (SKP1-Cullin1-F-box) complex - it shares SKP1 and an F-box subunit but lacks the defining cullin scaffold. The specific complex term GO:0030877 (beta-catenin destruction complex) is already accepted for this gene with IDA evidence, so the SCF complex assignment is a phylogenetic over-transfer from SKP1/F-box component sharing. Reason: The Siah1-based E3 complex is non-cullin and therefore not an SCF complex as defined by GO:0019005, even though it shares SKP1 and an F-box subunit. The more specific GO:0030877 (beta-catenin destruction complex) annotation already captures the actual complex membership accurately. Supporting Evidence: PMID:16085652 The E3 complex comprises, in addition to Siah1, Siah-interacting protein (SIP), the adaptor protein Skp1, and the F-box protein Ebi
GO:0031625 ubiquitin protein ligase binding	IBA GO_REF:0000033	ACCEPT	Summary: CACYBP binds the RING E3 ligases SIAH1/SIAH2 directly, a core molecular function underlying its bridging role. Reason: Direct interaction of CACYBP/SIP with Siah1 is structurally characterized and is central to assembly of the beta-catenin-destruction E3 complex. Supporting Evidence: PMID:16085652 SIP engages Siah1 by means of two elements
GO:0060090 molecular adaptor activity	IBA GO_REF:0000033	ACCEPT	Summary: CACYBP serves as a molecular bridge/adaptor in ubiquitin E3 complexes, bringing substrate and E2 into apposition; this is its core molecular function. Reason: CACYBP scaffolds Siah1 and Skp1 and provides the surface that brings substrate and the E2 enzyme together. Supporting Evidence: PMID:16085652 this surface provides the scaffold for bringing substrate and the E2 enzyme into apposition in the functional complex
GO:0007507 heart development	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Heart development is a broad developmental process not supported by direct mechanistic evidence for human CACYBP; the protein's documented role is as an E3 ligase adaptor. Reason: No direct evidence links CACYBP to heart development as a core function; this appears to be a phylogenetic/orthology-based broad transfer.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nuclear localization is supported by direct subcellular localization data. Reason: CACYBP localizes to the nucleus, especially after calcium increase. Supporting Evidence: file:human/CACYBP/CACYBP-uniprot.txt it localizes in both the nucleus and cytoplasm
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Cytoplasmic localization is well supported; CACYBP is cytoplasmic at low calcium concentrations. Reason: Direct localization data place CACYBP in the cytoplasm. Supporting Evidence: file:human/CACYBP/CACYBP-uniprot.txt Cytoplasmic at low calcium
GO:0015631 tubulin binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Tubulin binding is an InterPro-based electronic inference without direct human experimental support; cytoskeletal roles are reported but not as a clear core molecular function. Reason: No direct experimental evidence in the cached literature supports tubulin binding as a core CACYBP function; it is an automated domain-based transfer.
GO:0031625 ubiquitin protein ligase binding	IEA GO_REF:0000120	ACCEPT	Summary: CACYBP binds the E3 ligase Siah1 directly; core molecular function (consistent with the IBA annotation). Reason: Direct Siah1 interaction is structurally established. Supporting Evidence: PMID:16085652 SIP engages Siah1 by means of two elements
GO:0044548 S100 protein binding	IEA GO_REF:0000002	ACCEPT	Summary: Calcium-dependent binding to S100 family proteins (calcyclin/S100A6 and others) is the basis of the protein's name and a core molecular function linking calcium signaling to its ubiquitination machinery. Reason: CACYBP interacts with multiple S100 proteins in a calcium-dependent manner. Supporting Evidence: file:human/CACYBP/CACYBP-uniprot.txt Interacts with proteins of the S100 family S100A1, S100A6, S100B, S100P and S100A12 in a calcium-dependent manner
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput chaperone interaction (LUMIER) network; uninformative. Reason: Bare protein binding does not convey a specific CACYBP molecular function.
GO:0005515 protein binding	IPI PMID:31837246 High-throughput competitive fluorescence polarization assay ...	MARK AS OVER ANNOTATED	Summary: The underlying data are S100 family interaction profiling, but the GO term used is generic protein binding; S100 protein binding is the informative term. Reason: Bare protein binding is uninformative; the specific S100 binding is captured by GO:0044548.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from an EGFR-network interactome study; uninformative. Reason: Bare protein binding from a high-throughput screen does not identify a core CACYBP function.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the BioPlex proteome-scale interactome; uninformative. Reason: Bare protein binding is too general to represent CACYBP function.
GO:0005515 protein binding	IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a PDZ-affinity fragmentomics interactome; uninformative. Reason: Bare protein binding does not convey a specific CACYBP molecular function.
GO:0005641 nuclear envelope lumen	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Nuclear envelope lumen is an orthology-transferred localization with no direct support; inconsistent with the documented nucleoplasmic/cytoplasmic distribution. Reason: An automated Ensembl Compara transfer not supported by direct human localization evidence.
GO:0007507 heart development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Heart development is a broad orthology-transferred process without direct mechanistic support for human CACYBP. Reason: Automated transfer; CACYBP's core role is as an E3 ligase adaptor, not a defined cardiac developmental factor.
GO:0019005 SCF ubiquitin ligase complex	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: As for the IBA SCF complex annotation above, this is a non-cullin Siah1-based RING E3 ligase that shares SKP1/F-box subunits with SCF complexes but is not itself an SCF complex (no cullin scaffold). The specific GO:0030877 (beta-catenin destruction complex) is the accurate term. Reason: Same rationale as the IBA SCF annotation - the Siah1 E3 complex is non-cullin and therefore not an SCF complex as defined by GO:0019005. Supporting Evidence: PMID:16085652 the adaptor protein Skp1, and the F-box protein Ebi
GO:0019904 protein domain specific binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Protein domain specific binding is a broad orthology-transferred molecular function without specific support; more informative terms (Siah1 binding, S100 binding) are captured elsewhere. Reason: Too general and automatically transferred; superseded by the specific binding terms.
GO:0044297 cell body	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cell body is an orthology-transferred neuronal localization without direct human support. Reason: Automated Ensembl Compara transfer not supported by direct evidence for human CACYBP.
GO:0045740 positive regulation of DNA replication	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Positive regulation of DNA replication is a broad orthology-transferred process not supported by direct mechanistic evidence for human CACYBP. Reason: Automated transfer; not a documented core function.
GO:0055007 cardiac muscle cell differentiation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cardiac muscle cell differentiation is an orthology-transferred developmental process without direct support for human CACYBP. Reason: Automated transfer; not a documented core function.
GO:0060416 response to growth hormone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to growth hormone is an orthology-transferred process without direct mechanistic support for human CACYBP. Reason: Automated transfer; not a documented core function.
GO:0071277 cellular response to calcium ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Cellular response to calcium ion is consistent with CACYBP's calcium-dependent S100 binding and calcium-regulated localization, but the term is broad and the annotation is an orthology transfer. Reason: The calcium-dependence of CACYBP function is real, but this broad process term is best retained as non-core relative to its E3-adaptor molecular role. Supporting Evidence: file:human/CACYBP/CACYBP-uniprot.txt in a calcium-dependent manner
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Nucleoplasmic localization is supported by direct immunofluorescence and the documented nuclear redistribution. Reason: CACYBP localizes to the nucleus, consistent with nucleoplasmic detection. Supporting Evidence: file:human/CACYBP/CACYBP-uniprot.txt it localizes in both the nucleus and cytoplasm
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosolic localization is well supported; CACYBP is cytoplasmic at low calcium. Reason: Direct localization data place CACYBP in the cytosol. Supporting Evidence: file:human/CACYBP/CACYBP-uniprot.txt Cytoplasmic at low calcium
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	MARK AS OVER ANNOTATED	Summary: High-throughput exosome proteomics localization; not a functionally meaningful localization for a nucleocytoplasmic E3-adaptor protein. Reason: Mass-spectrometry co-purification hit without evidence for a functional extracellular/exosomal role.
GO:0005515 protein binding	IPI PMID:16085652 Structural analysis of Siah1-Siah-interacting protein intera...	MARK AS OVER ANNOTATED	Summary: The underlying evidence is the specific CACYBP/SIP-Siah1 and CACYBP-Skp1 interactions; the generic protein binding term is uninformative relative to those specific terms. Reason: Bare protein binding is too general; the informative interactions (Siah1/ubiquitin protein ligase binding, adaptor activity) are captured by other terms.
GO:0030877 beta-catenin destruction complex	IDA PMID:16085652 Structural analysis of Siah1-Siah-interacting protein intera...	ACCEPT	Summary: CACYBP/SIP is a component of the Siah1-based complex that targets beta-catenin for degradation; core function. Reason: CACYBP is directly shown to be part of the multiprotein E3 complex that destroys beta-catenin in response to p53. Supporting Evidence: PMID:16085652 a multiprotein E3 ubiquitin ligase complex that targets beta-catenin for destruction in response to p53 activation
GO:0042803 protein homodimerization activity	IPI PMID:16085652 Structural analysis of Siah1-Siah-interacting protein intera...	ACCEPT	Summary: CACYBP/SIP forms a homodimer via its N-terminal dimerization domain, which is required for Siah1 binding and beta-catenin destruction; core molecular property. Reason: The N-terminal dimerization domain of SIP is structurally characterized and functionally required. Supporting Evidence: PMID:16085652 An N-terminal dimerization domain of SIP sits across the saddle-shaped upper surface of Siah1

Core Functions

Acts as a molecular adaptor/bridge that assembles a Siah1/Siah2-based, SKP1-containing E3 ubiquitin ligase complex, bringing substrate and the E2 enzyme into apposition to enable ubiquitination and proteasomal degradation of targets.

Molecular Function:

molecular adaptor activity

In Complex:

beta-catenin destruction complex

Supporting Evidence:

PMID:16085652
this surface provides the scaffold for bringing substrate and the E2 enzyme into apposition in the functional complex

Binds the RING E3 ligase Siah1 (and Siah2) directly via an N-terminal dimerization domain and a Siah-binding motif, a core interaction for E3 complex assembly and beta-catenin degradation.

Molecular Function:

ubiquitin protein ligase binding

Supporting Evidence:

PMID:16085652
SIP engages Siah1 by means of two elements

Binds S100 family proteins (calcyclin/S100A6 and others) in a calcium-dependent manner, linking calcium signaling to the ubiquitination machinery.

Molecular Function:

S100 protein binding

Supporting Evidence:

file:human/CACYBP/CACYBP-uniprot.txt
Interacts with proteins of the S100 family S100A1, S100A6, S100B, S100P and S100A12 in a calcium-dependent manner

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16085652

Structural analysis of Siah1-Siah-interacting protein interactions and insights into the assembly of an E3 ligase multiprotein complex.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

PMID:31837246

High-throughput competitive fluorescence polarization assay reveals functional redundancy in the S100 protein family.

PMID:31980649

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:36115835

Quantitative fragmentomics allow affinity mapping of interactomes.

PMID:18803400

Structure of the S100A6 complex with a fragment from the C-terminal domain of Siah-1 interacting protein: a novel mode for S100 protein target recognition.

NMR/ITC structure of the Ca2+-loaded S100A6 complex with CACYBP/SIP(189-219) shows S100A6 binds the C-terminal SGS region of SIP in a strictly calcium-dependent manner, with a minimal binding fragment Ser189-Arg219; SIP is described as a scaffold in an SCF-like (SCF-TBL1) E3 ligase that links the Siah-1 module to the Skp1-TBL1 substrate-recruiting module.

PMID:22295074

S100A6 protein negatively regulates CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation and tumorigenesis.

Overexpression of CacyBP/SIP inhibits gastric cancer cell proliferation and tumorigenesis, an effect strengthened by deleting the S100-binding domain; S100 binding negatively regulates this anti-proliferative activity through reduction of beta-catenin protein and Tcf/LEF transcriptional activity, and the beta-catenin reduction is proteasome-dependent (reversed by MG132).

PMID:24078263

The CacyBP/SIP protein is sumoylated in neuroblastoma NB2a cells.

CacyBP/SIP binds the SUMO E2 enzyme Ubc9 and is SUMO1-modified at Lysine 16 (abolished by the K16R mutation); atypically, the SUMO-conjugated form is enriched in the cytoplasmic rather than the nuclear fraction.

PMID:38322570

Pan-analysis reveals CACYBP to be a novel prognostic and predictive marker for multiple cancers.

Integrative pan-cancer analysis reports CACYBP is differentially expressed across many cancer types (upregulated in 14, downregulated in 6), associated with prognosis in 13 cancers and with tumor mutational burden, microsatellite instability, and immune infiltration, with protein-level upregulation validated in paired lung adenocarcinoma specimens.

Suggested Experiments

Experiment: Reconstitute the Siah1-CACYBP-Skp1-Ebi E3 complex in vitro and test whether calcium-loaded S100A6 binding to CACYBP enhances or inhibits beta-catenin ubiquitination, to define the calcium-to-ubiquitination coupling.

Experiment: Perform quantitative degradomics in CACYBP-knockout vs wild-type cells under calcium stimulation to identify the substrate repertoire dependent on CACYBP.

Experiment: Test for direct, purified-protein phosphatase activity of CACYBP/SIP toward phospho-ERK1/2 in vitro, and determine whether PKC/CKII phosphorylation or Ca2+/S100A6 binding modulate this activity, to confirm or refute the proposed ERK1/2 phosphatase function independent of the E3-adaptor role.

Deep Research

Falcon

(CACYBP-deep-research-falcon.md)

Research Report: Human **CACYBP** (Calcyclin-binding protein; UniProt **Q9HB71**) Falcon Edison Scientific Literature 28 citations 2 artifacts 2026-06-07T05:27:26.030095

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000030 The domain architecture and interaction of SIP/CacyBP with S100A6 are illustrated in Figures 2 and 5. Figure 2a provides a schemati (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human CACYBP (Calcyclin-binding protein; UniProt Q9HB71)

0) Target verification (mandatory)

The requested target is human CACYBP (UniProt Q9HB71), also widely referred to in the literature as CacyBP/SIP (calcyclin-binding protein / Siah-1–interacting protein) and as an S100A6-binding protein. Foundational structural and mechanistic studies define it as a modular, multi-domain adaptor/scaffold protein that binds S100A6 (calcyclin) in a strictly Ca2+-dependent manner and interfaces with Siah-1 and Skp1 in an SCF-like E3 ubiquitin ligase module (lee2008structureofthe pages 1-2, ning2012s100a6proteinnegatively pages 1-2). Because many early studies use mouse/rat tissues or rodent cell lines while using the same name/symbol, careful species/orthology checking is required; nevertheless, the molecular identity (S100A6 ligand; Siah-interacting; modular domains) is consistent across mammalian literature (wasik2013thecacybpsipprotein pages 1-2, filipek2018currentviewon pages 3-4).

1) Key concepts and current understanding (definitions + primary function)

1.1 What CACYBP is (conceptual definition)

CACYBP is best understood as a Ca2+-regulated adaptor/scaffold that integrates:

1) Ca2+/S100 signaling (via Ca2+-dependent binding to S100A6),
2) ubiquitin-mediated proteostasis (via association with Siah-1/Skp1-containing E3 ligase assemblies and modulation of β-catenin stability), and
3) MAPK signaling control (via reported phosphatase activity affecting ERK1/2-dependent transcriptional outputs) (filipek2018currentviewon pages 4-5, lee2008structureofthe pages 1-2, wasik2013thecacybpsipprotein pages 1-2).

Unlike enzymes with a well-defined small-molecule substrate, CACYBP’s “primary function” is protein–protein interaction–driven scaffolding/regulation, influencing substrate selection and signaling state through complex assembly and post-translational modifications (filipek2018currentviewon pages 4-5, lee2008structureofthe pages 1-2).

1.2 Domain architecture (mechanistic definition)

A key mechanistic advance is the domain-level mapping of CACYBP/SIP:

N-terminal helical hairpin domain (M1–N78)
Central CS/p23-like domain (Y79–K177)
C-terminal SGS region (E178–F229), described as intrinsically disordered but forming helices upon binding S100A6 (lee2008structureofthe pages 1-2).

This architecture is depicted in the original structural paper’s figures (lee2008structureofthe media 3829c55f, lee2008structureofthe media 18fa429a).

1.3 Ca2+-dependent binding to S100A6 (calcyclin)

CACYBP/SIP was structurally characterized in complex with Ca2+-loaded S100A6, revealing that:

S100A6 binds the C-terminal SGS region of SIP in a strictly Ca2+-dependent fashion.
A minimal binding fragment mapped to Ser189–Arg219.
NMR structural work shows this peptide adopts two helices that engage S100A6, including a novel binding mode across the S100A6 dimer interface (lee2008structureofthe pages 1-2).

These features support the view that CACYBP can act as a Ca2+-regulated interaction hub whose downstream effects may depend on intracellular Ca2+ and S100A6 activation state (lee2008structureofthe pages 1-2).

1.4 Ubiquitin–proteasome pathway: SCF-like E3 ligase module and β-catenin regulation

Multiple lines of evidence support CACYBP/SIP as a scaffold component in an SCF-like E3 ubiquitin ligase context:

Structural/mechanistic framing proposes a SCF-TBL1–like E3 ligase assembly under genotoxic stress, with SIP/CACYBP linking Siah-1 (E2-recruiting factor) to a Skp1–TBL1 substrate-recruitment module, enabling poly-ubiquitination and proteasome-dependent degradation of β-catenin in a phosphorylation-independent manner (lee2008structureofthe pages 1-2).
In gastric cancer models, CacyBP/SIP is described as part of an Siah1–CacyBP/SIP–Skp1 E3 ligase complex promoting degradation of unphosphorylated β-catenin. Importantly, proteasome inhibition (MG132) reverses β-catenin reduction driven by a CacyBP/SIP construct lacking the S100-binding domain, supporting a proteasome-dependent mechanism (ning2012s100a6proteinnegatively pages 4-6).
The same study provides domain mapping consistent with modular scaffolding: N-terminus for Siah1 binding, mid-region for Skp1 binding, and C-terminus for S100 binding; and demonstrates that removing the S100-binding domain can strengthen the anti-proliferative phenotype (ning2012s100a6proteinnegatively pages 1-2, ning2012s100a6proteinnegatively pages 4-6).

Collectively, current understanding supports CACYBP as a regulator of β-catenin stability via ubiquitin–proteasome complex assembly, with S100A6 binding acting as a negative regulator in some contexts (filipek2018currentviewon pages 4-5, ning2012s100a6proteinnegatively pages 4-6).

1.5 MAPK signaling: ERK1/2-associated phosphatase activity and regulation

CACYBP/SIP is repeatedly described as interacting with ERK1/2 and modulating downstream transcription:

In neuroblastoma systems, CacyBP/SIP is reported to interact with ERK1/2 and inhibit phosphorylation of Elk-1, an effect attributed to CacyBP/SIP phosphatase activity toward ERK1/2 (wasik2013thecacybpsipprotein pages 1-2).
A mechanistic review summarizes additional regulation by post-translational modifications: PKC phosphorylation at Ser22/Thr23 increases phosphatase activity toward ERK1/2; CKII phosphorylation at Thr184 is described, and Ca2+/S100A6 binding can inhibit Thr184 phosphorylation; sumoylation at Lys16 also occurs (filipek2018currentviewon pages 4-5).

Taken together, CACYBP is positioned as a signaling-state modulator connecting Ca2+/S100 signaling and MAPK pathway output (filipek2018currentviewon pages 4-5, wasik2013thecacybpsipprotein pages 1-2).

1.6 Cytoskeleton interactions and cellular remodeling

CacyBP/SIP is a multi-ligand protein with reported binding partners including tubulin, actin, tropomyosin, and tau (filipek2018currentviewon pages 4-5, wasik2013thecacybpsipprotein pages 1-2). Reviews connect these interactions to neurite outgrowth, differentiation, and cytoskeletal organization (filipek2018currentviewon pages 3-4, filipek2018currentviewon pages 4-5). Although some of the most detailed cytoskeletal mechanistic primary papers were not directly retrievable in this run, the presence of these interactions is consistently cited and integrated into the functional model (ning2012s100a6proteinnegatively pages 8-8, filipek2018currentviewon pages 4-5).

2) Subcellular localization and where CACYBP acts in the cell

2.1 Basal localization and regulated translocation

CacyBP/SIP is described as predominantly cytosolic in mammalian cell models, but it can relocalize:

A review summarizes that it can translocate to perinuclear regions and to the nucleus in response to increased intracellular Ca2+, retinoic acid, and oxidative stress (filipek2018currentviewon pages 4-5, filipek2018currentviewon pages 3-4).

2.2 SUMOylation and compartmentalization

Direct experimental evidence in NB2a cells shows that CacyBP/SIP is SUMOylated:

CacyBP/SIP binds the SUMO E2 enzyme Ubc9 and is SUMO1-modified.
Mutational analysis identifies Lys16 as the SUMO acceptor (K16R abolishes SUMOylation).
Subcellular fractionation shows the SUMO-conjugated form (reported as an additional band at ~75 kDa) is present in the cytoplasmic fraction rather than the nuclear fraction, which is atypical for many SUMO-modified proteins (wasik2013thecacybpsipprotein pages 2-4, wasik2013thecacybpsipprotein pages 4-6).

A review further connects CacyBP/SIP to stress response and nucleolar biology:

Oxidative stressors (H2O2) and the Hsp90 inhibitor radicicol were reported to increase CacyBP/SIP protein levels by ~40–50% in cited systems.
CacyBP/SIP is described as required to maintain NPM1 abundance and nucleolar structure under oxidative stress in NB2a cells (filipek2018currentviewon pages 5-6).

3) Recent developments (prioritizing 2023–2024)

3.1 2024 pan-cancer translational evidence: prognostic/predictive biomarker potential

A 2024 pan-cancer study (Mo et al., Jan 2024) compiled large TCGA/GTEx-centric analyses:

Sample sizes: described as 18,787 total samples, including 10,080 GTEx/TCGA-profiled samples (with TCGA: 9358 cancer, 722 controls) and GTEx normals (8671) (mo2024pananalysisrevealscacybp pages 1-2).
Expression patterns: CACYBP upregulated in 14 cancer types and downregulated in 6 (P < 0.05) (mo2024pananalysisrevealscacybp pages 1-2).
Diagnostic performance: CACYBP discriminated tumor vs normal with AUC > 0.80 in 15/21 cancers; an overall AUC of 0.95 (95% CI 0.92–0.96) is reported; some summaries note a 0.97 AUC (mo2024pananalysisrevealscacybp pages 5-10).
Clinical associations: significant association with AJCC stage in nine cancers (P < 0.05) and multiple survival endpoints (OS/DSS/DFI/PFI) in cancer-type-specific directions (mo2024pananalysisrevealscacybp pages 5-10).
Immunogenomic context: associations with TMB, MSI, neoantigen counts, and immune infiltration measures in selected tumor types (mo2024pananalysisrevealscacybp pages 5-10).
Protein-level validation: Western blotting in six paired LUAD specimens showed higher CacyBP protein in tumor vs adjacent tissue (P < 0.05) (mo2024pananalysisrevealscacybp pages 1-2).

Interpretation: these data represent real-world translational implementation primarily as a computational biomarker candidate (diagnostic/prognostic/predictive), but causal mechanism remains context-dependent and requires targeted functional validation in each cancer type (mo2024pananalysisrevealscacybp pages 10-13).

3.2 2023 reviews on S100A6 biology integrate CACYBP as a central ligand/effector

Two 2023 reviews (International Journal of Molecular Sciences; Biomarker Research) synthesize S100A6 biology and repeatedly contextualize CacyBP/SIP as a key S100A6 ligand involved in intracellular networks, including competition with ERK1/2 for binding and the β-catenin ubiquitination axis (lesniak2023s100a6protein—expressionand pages 13-15, wang2023s100a6molecularfunction pages 1-2). These reviews function as expert consensus summaries that the S100A6–CACYBP interaction is Ca2+-dependent and mechanistically connected to broader proteostasis and signaling systems (wang2023s100a6molecularfunction pages 1-2, wang2023s100a6molecularfunction pages 11-12).

3.3 2024 neurodegeneration/proteostasis framing (expert review)

A 2024 review on Alzheimer’s disease chaperones positions CacyBP/SIP (discussed as an Hsp90 co-chaperone module) among proteins whose dysfunction is implicated in AD pathogenesis, within a broader discussion of proteostasis, Aβ toxicity, and tau aggregation as therapeutic targets (batko2024chaperones—anewclass pages 1-2). This source is authoritative synthesis, but the excerpt available in this run does not provide quantitative CACYBP-specific datasets.

4) Current applications and real-world implementations

4.1 Cancer biomarker research workflows

The Mo et al. 2024 study illustrates a typical modern pipeline for candidate biomarkers: combining TCGA/GTEx expression contrasts, survival modeling, ROC/AUC diagnostics, and immune deconvolution (TIMER/ESTIMATE) to nominate genes for follow-up (mo2024pananalysisrevealscacybp pages 1-2, mo2024pananalysisrevealscacybp pages 5-10). In real-world terms, CACYBP is being used as a computationally derived candidate marker and as a target for small-scale protein validation (mo2024pananalysisrevealscacybp pages 1-2).

4.2 Mechanism-informed cancer biology (β-catenin axis)

The gastric cancer study provides a mechanistic application that can inform functional annotation and therapeutic reasoning:

Overexpression of CacyBP/SIP inhibited gastric cancer cell proliferation and tumorigenesis, and removing the S100-binding domain strengthened this phenotype.
Effects on β-catenin and Tcf/LEF transcription were proteasome-dependent, as MG132 reversed β-catenin reduction (ning2012s100a6proteinnegatively pages 4-6).

This provides a concrete, mechanistically anchored use case of CACYBP as a regulator of growth phenotypes via β-catenin proteostasis (ning2012s100a6proteinnegatively pages 4-6).

4.3 Clinical trials and patents

A search of ClinicalTrials.gov-style records returned no clearly relevant interventional trials directly targeting CACYBP (no relevant trials identified in the retrieved set).
Patent retrieval in this run did not yield text evidence that the retrieved patents explicitly claim CACYBP as a core diagnostic marker or therapeutic target (no relevant evidence found in the extracted patent texts).

5) Expert opinions and synthesis (authoritative perspectives)

Expert review literature emphasizes that CacyBP/SIP sits at the intersection of Ca2+-dependent S100 signaling, ubiquitin-mediated proteostasis, cytoskeletal remodeling, and stress response. Reviews characterize it as a multi-ligand, multi-domain hub with context-dependent functional outputs, including regulated phosphatase activity and modulated participation in ubiquitin ligase assemblies; S100A6 binding is framed as a key regulatory input (filipek2018currentviewon pages 4-5, filipek2018currentviewon pages 3-4, wang2023s100a6molecularfunction pages 1-2).

6) Quantitative statistics and data highlights (recent + mechanistic)

Pan-cancer dataset sizes: 18,787 total samples; 10,080 GTEx/TCGA-profiled samples (TCGA 9358 cancer, 722 controls; GTEx 8671 normals) (mo2024pananalysisrevealscacybp pages 1-2).
Diagnostic ROC performance: overall AUC 0.95 (95% CI 0.92–0.96) across 21 cancer types; AUC > 0.80 in 15/21 cancers (mo2024pananalysisrevealscacybp pages 5-10).
Protein-level validation: n = 6 paired LUAD specimens with higher CacyBP protein in tumor vs adjacent tissue (P < 0.05) (mo2024pananalysisrevealscacybp pages 1-2).
SUMOylation biochemical readout: SUMO-conjugated CacyBP band observed at ~75 kDa and enriched in cytoplasmic fraction; K16R mutant abolishes this modification (wasik2013thecacybpsipprotein pages 2-4, wasik2013thecacybpsipprotein pages 4-6).
Stress-induced abundance change: CacyBP/SIP protein level reportedly increases ~40–50% under H2O2/radicicol conditions in cited systems (filipek2018currentviewon pages 5-6).

7) Visual evidence (structural/domain mapping)

The structural paper’s figures provide direct visual support for CACYBP’s modular architecture and S100A6 binding geometry:

Domain schematic and mapping of S100A6-binding helices in the SGS region (lee2008structureofthe media 3829c55f)
NMR structure of Ca2+-S100A6 dimer bound to SIP(189–219) peptides (lee2008structureofthe media 18fa429a)

8) Summary for functional annotation (concise)

CACYBP (Q9HB71) is a cytosolic, Ca2+-responsive scaffold/adaptor that binds S100A6 via its C-terminal SGS region and participates in protein complex assembly affecting β-catenin ubiquitin–proteasome turnover and MAPK (ERK1/2) signaling output, with additional interactions with cytoskeletal proteins and stress/nucleolar pathways. Its regulated localization (cytosol ↔ perinuclear/nucleus) and PTMs (notably SUMOylation at Lys16) support dynamic, condition-dependent functions. Recent 2024 large-scale analyses highlight CACYBP’s potential value as a multi-cancer diagnostic/prognostic marker (lee2008structureofthe pages 1-2, ning2012s100a6proteinnegatively pages 4-6, wasik2013thecacybpsipprotein pages 1-2, filipek2018currentviewon pages 4-5, wasik2013thecacybpsipprotein pages 2-4, mo2024pananalysisrevealscacybp pages 5-10).

Key sources (URLs; publication dates)

Lee Y-T et al. Biochemistry (Oct 2008). Structure of the S100A6 complex with a fragment from the C-terminal domain of Siah-1 interacting protein. https://doi.org/10.1021/bi801233z (lee2008structureofthe pages 1-2)
Ning X et al. PLOS ONE (Jan 2012). S100A6 negatively regulates CacyBP/SIP-mediated inhibition of gastric cancer proliferation and tumorigenesis. https://doi.org/10.1371/journal.pone.0030185 (ning2012s100a6proteinnegatively pages 4-6)
Wasik U, Filipek A. Neurochemical Research (Sep 2013). The CacyBP/SIP protein is sumoylated in neuroblastoma NB2a cells. https://doi.org/10.1007/s11064-013-1155-4 (wasik2013thecacybpsipprotein pages 2-4)
Filipek A, Leśniak W. Postępy Biochemii (Dec 2018). Current view on cellular function of S100A6 and its ligands, CacyBP/SIP and Sgt1. https://doi.org/10.18388/pb.2018_136 (filipek2018currentviewon pages 4-5)
Wang Y et al. Biomarker Research (Sep 2023). S100A6: molecular function and biomarker role. https://doi.org/10.1186/s40364-023-00515-3 (wang2023s100a6molecularfunction pages 1-2)
Leśniak W, Filipek A. Int J Mol Sci (Jan 2023). S100A6 Protein—Expression and Function in Norm and Pathology. https://doi.org/10.3390/ijms24021341 (lesniak2023s100a6protein—expressionand pages 13-15)
Mo B et al. Am J Transl Res (Jan 2024). Pan-analysis reveals CACYBP to be a novel prognostic and predictive marker for multiple cancers. https://doi.org/10.62347/owvw7440 (mo2024pananalysisrevealscacybp pages 1-2)
Batko J et al. Int J Mol Sci (Mar 2024). Chaperones—A New Class of Potential Therapeutic Targets in Alzheimer’s Disease. https://doi.org/10.3390/ijms25063401 (batko2024chaperones—anewclass pages 1-2)

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 (lee2008structureofthe pages 1-2, filipek2018currentviewon pages 1-2, wang2023s100a6molecularfunction pages 1-2)
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 (lee2008structureofthe pages 1-2, ning2012s100a6proteinnegatively pages 1-2, ning2012s100a6proteinnegatively pages 4-6, filipek2018currentviewon pages 4-5, wang2023s100a6molecularfunction pages 11-12)
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 (wasik2013thecacybpsipprotein pages 1-2, filipek2018currentviewon pages 4-5)
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 (filipek2018currentviewon pages 3-4, ning2012s100a6proteinnegatively pages 8-8, wasik2013thecacybpsipprotein pages 1-2)
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 (wasik2013thecacybpsipprotein pages 1-2, wasik2013thecacybpsipprotein pages 2-4, wasik2013thecacybpsipprotein pages 4-6, filipek2018currentviewon pages 4-5, filipek2018currentviewon pages 5-6)
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 (mo2024pananalysisrevealscacybp pages 5-10, mo2024pananalysisrevealscacybp pages 1-2, mo2024pananalysisrevealscacybp pages 13-14, mo2024pananalysisrevealscacybp pages 10-13)

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.

References

(lee2008structureofthe pages 1-2): Young-Tae Lee, Yoana N. Dimitrova, Gabriela Schneider, Whitney B. Ridenour, Shibani Bhattacharya, Sarah E. Soss, Richard M. Caprioli, Anna Filipek, and Walter J. Chazin. Structure of the s100a6 complex with a fragment from the c-terminal domain of siah-1 interacting protein: a novel mode for s100 protein target recognition. Biochemistry, 47 41:10921-32, Oct 2008. URL: https://doi.org/10.1021/bi801233z, doi:10.1021/bi801233z. This article has 80 citations and is from a peer-reviewed journal.
(ning2012s100a6proteinnegatively pages 1-2): Xiaoxuan Ning, Shiren Sun, Kun Zhang, Jie Liang, Yucai Chuai, Yuan Li, and Xiaoming Wang. S100a6 protein negatively regulates cacybp/sip-mediated inhibition of gastric cancer cell proliferation and tumorigenesis. PLoS ONE, 7:e30185, Jan 2012. URL: https://doi.org/10.1371/journal.pone.0030185, doi:10.1371/journal.pone.0030185. This article has 54 citations and is from a peer-reviewed journal.
(wasik2013thecacybpsipprotein pages 1-2): Urszula Wasik and Anna Filipek. The cacybp/sip protein is sumoylated in neuroblastoma nb2a cells. Neurochemical Research, 38:2427-2432, Sep 2013. URL: https://doi.org/10.1007/s11064-013-1155-4, doi:10.1007/s11064-013-1155-4. This article has 11 citations and is from a peer-reviewed journal.
(filipek2018currentviewon pages 3-4): Anna Filipek and Wiesława Leśniak. Current view on cellular function of s100a6 and its ligands, cacybp/sip and sgt1. Postepy biochemii, 64 3:242-252, Dec 2018. URL: https://doi.org/10.18388/pb.2018_136, doi:10.18388/pb.2018_136. This article has 19 citations.
(filipek2018currentviewon pages 4-5): Anna Filipek and Wiesława Leśniak. Current view on cellular function of s100a6 and its ligands, cacybp/sip and sgt1. Postepy biochemii, 64 3:242-252, Dec 2018. URL: https://doi.org/10.18388/pb.2018_136, doi:10.18388/pb.2018_136. This article has 19 citations.
(lee2008structureofthe media 3829c55f): Young-Tae Lee, Yoana N. Dimitrova, Gabriela Schneider, Whitney B. Ridenour, Shibani Bhattacharya, Sarah E. Soss, Richard M. Caprioli, Anna Filipek, and Walter J. Chazin. Structure of the s100a6 complex with a fragment from the c-terminal domain of siah-1 interacting protein: a novel mode for s100 protein target recognition. Biochemistry, 47 41:10921-32, Oct 2008. URL: https://doi.org/10.1021/bi801233z, doi:10.1021/bi801233z. This article has 80 citations and is from a peer-reviewed journal.
(lee2008structureofthe media 18fa429a): Young-Tae Lee, Yoana N. Dimitrova, Gabriela Schneider, Whitney B. Ridenour, Shibani Bhattacharya, Sarah E. Soss, Richard M. Caprioli, Anna Filipek, and Walter J. Chazin. Structure of the s100a6 complex with a fragment from the c-terminal domain of siah-1 interacting protein: a novel mode for s100 protein target recognition. Biochemistry, 47 41:10921-32, Oct 2008. URL: https://doi.org/10.1021/bi801233z, doi:10.1021/bi801233z. This article has 80 citations and is from a peer-reviewed journal.
(ning2012s100a6proteinnegatively pages 4-6): Xiaoxuan Ning, Shiren Sun, Kun Zhang, Jie Liang, Yucai Chuai, Yuan Li, and Xiaoming Wang. S100a6 protein negatively regulates cacybp/sip-mediated inhibition of gastric cancer cell proliferation and tumorigenesis. PLoS ONE, 7:e30185, Jan 2012. URL: https://doi.org/10.1371/journal.pone.0030185, doi:10.1371/journal.pone.0030185. This article has 54 citations and is from a peer-reviewed journal.
(ning2012s100a6proteinnegatively pages 8-8): Xiaoxuan Ning, Shiren Sun, Kun Zhang, Jie Liang, Yucai Chuai, Yuan Li, and Xiaoming Wang. S100a6 protein negatively regulates cacybp/sip-mediated inhibition of gastric cancer cell proliferation and tumorigenesis. PLoS ONE, 7:e30185, Jan 2012. URL: https://doi.org/10.1371/journal.pone.0030185, doi:10.1371/journal.pone.0030185. This article has 54 citations and is from a peer-reviewed journal.
(wasik2013thecacybpsipprotein pages 2-4): Urszula Wasik and Anna Filipek. The cacybp/sip protein is sumoylated in neuroblastoma nb2a cells. Neurochemical Research, 38:2427-2432, Sep 2013. URL: https://doi.org/10.1007/s11064-013-1155-4, doi:10.1007/s11064-013-1155-4. This article has 11 citations and is from a peer-reviewed journal.
(wasik2013thecacybpsipprotein pages 4-6): Urszula Wasik and Anna Filipek. The cacybp/sip protein is sumoylated in neuroblastoma nb2a cells. Neurochemical Research, 38:2427-2432, Sep 2013. URL: https://doi.org/10.1007/s11064-013-1155-4, doi:10.1007/s11064-013-1155-4. This article has 11 citations and is from a peer-reviewed journal.
(filipek2018currentviewon pages 5-6): Anna Filipek and Wiesława Leśniak. Current view on cellular function of s100a6 and its ligands, cacybp/sip and sgt1. Postepy biochemii, 64 3:242-252, Dec 2018. URL: https://doi.org/10.18388/pb.2018_136, doi:10.18388/pb.2018_136. This article has 19 citations.
(mo2024pananalysisrevealscacybp pages 1-2): Baosen Mo, Bijun Luo, and Yuesong Wu. Pan-analysis reveals cacybp to be a novel prognostic and predictive marker for multiple cancers. American journal of translational research, 16 1:12-26, Jan 2024. URL: https://doi.org/10.62347/owvw7440, doi:10.62347/owvw7440. This article has 6 citations and is from a peer-reviewed journal.
(mo2024pananalysisrevealscacybp pages 5-10): Baosen Mo, Bijun Luo, and Yuesong Wu. Pan-analysis reveals cacybp to be a novel prognostic and predictive marker for multiple cancers. American journal of translational research, 16 1:12-26, Jan 2024. URL: https://doi.org/10.62347/owvw7440, doi:10.62347/owvw7440. This article has 6 citations and is from a peer-reviewed journal.
(mo2024pananalysisrevealscacybp pages 10-13): Baosen Mo, Bijun Luo, and Yuesong Wu. Pan-analysis reveals cacybp to be a novel prognostic and predictive marker for multiple cancers. American journal of translational research, 16 1:12-26, Jan 2024. URL: https://doi.org/10.62347/owvw7440, doi:10.62347/owvw7440. This article has 6 citations and is from a peer-reviewed journal.
(lesniak2023s100a6protein—expressionand pages 13-15): Wiesława Leśniak and Anna Filipek. S100a6 protein—expression and function in norm and pathology. International Journal of Molecular Sciences, 24:1341, Jan 2023. URL: https://doi.org/10.3390/ijms24021341, doi:10.3390/ijms24021341. This article has 30 citations.
(wang2023s100a6molecularfunction pages 1-2): Yidian Wang, Xuewen Kang, Xin Kang, and Fengguang Yang. S100a6: molecular function and biomarker role. Biomarker Research, Sep 2023. URL: https://doi.org/10.1186/s40364-023-00515-3, doi:10.1186/s40364-023-00515-3. This article has 54 citations and is from a peer-reviewed journal.
(wang2023s100a6molecularfunction pages 11-12): Yidian Wang, Xuewen Kang, Xin Kang, and Fengguang Yang. S100a6: molecular function and biomarker role. Biomarker Research, Sep 2023. URL: https://doi.org/10.1186/s40364-023-00515-3, doi:10.1186/s40364-023-00515-3. This article has 54 citations and is from a peer-reviewed journal.
(batko2024chaperones—anewclass pages 1-2): Joanna Batko, Katarzyna Antosz, Weronika Miśków, Magdalena Pszczołowska, Kamil Walczak, and Jerzy Leszek. Chaperones—a new class of potential therapeutic targets in alzheimer’s disease. International Journal of Molecular Sciences, 25:3401, Mar 2024. URL: https://doi.org/10.3390/ijms25063401, doi:10.3390/ijms25063401. This article has 41 citations.
(filipek2018currentviewon pages 1-2): Anna Filipek and Wiesława Leśniak. Current view on cellular function of s100a6 and its ligands, cacybp/sip and sgt1. Postepy biochemii, 64 3:242-252, Dec 2018. URL: https://doi.org/10.18388/pb.2018_136, doi:10.18388/pb.2018_136. This article has 19 citations.
(mo2024pananalysisrevealscacybp pages 13-14): Baosen Mo, Bijun Luo, and Yuesong Wu. Pan-analysis reveals cacybp to be a novel prognostic and predictive marker for multiple cancers. American journal of translational research, 16 1:12-26, Jan 2024. URL: https://doi.org/10.62347/owvw7440, doi:10.62347/owvw7440. This article has 6 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

lee2008structureofthe pages 1-2
wasik2013thecacybpsipprotein pages 1-2
filipek2018currentviewon pages 4-5
filipek2018currentviewon pages 5-6
mo2024pananalysisrevealscacybp pages 1-2
mo2024pananalysisrevealscacybp pages 5-10
mo2024pananalysisrevealscacybp pages 10-13
wasik2013thecacybpsipprotein pages 2-4
filipek2018currentviewon pages 3-4
wasik2013thecacybpsipprotein pages 4-6
filipek2018currentviewon pages 1-2
mo2024pananalysisrevealscacybp pages 13-14
https://doi.org/10.1021/bi801233z
https://doi.org/10.1371/journal.pone.0030185
https://doi.org/10.1007/s11064-013-1155-4
https://doi.org/10.18388/pb.2018_136
https://doi.org/10.1186/s40364-023-00515-3
https://doi.org/10.3390/ijms24021341
https://doi.org/10.62347/owvw7440
https://doi.org/10.3390/ijms25063401
https://doi.org/10.1021/bi801233z,
https://doi.org/10.1371/journal.pone.0030185,
https://doi.org/10.1007/s11064-013-1155-4,
https://doi.org/10.18388/pb.2018_136,
https://doi.org/10.62347/owvw7440,
https://doi.org/10.3390/ijms24021341,
https://doi.org/10.1186/s40364-023-00515-3,
https://doi.org/10.3390/ijms25063401,

📚 Additional Documentation

Notes

(CACYBP-notes.md)

CACYBP (Calcyclin-Binding Protein / SIP / Siah-Interacting Protein) — research notes

UniProt: Q9HB71 (CYBP_HUMAN). Synonyms: S100A6BP, SIP, S100A6-binding protein, Siah-interacting protein.
HGNC. Aliases SIP = Siah-Interacting Protein.

Core molecular/cellular function: adaptor/bridge in a Siah1-based E3 ubiquitin ligase complex

CACYBP/SIP serves as a molecular bridge in ubiquitin E3 complexes, participating in calcium-dependent ubiquitination and proteasomal degradation of target proteins, notably beta-catenin (CTNNB1).
[file:human/CACYBP/CACYBP-uniprot.txt "May be involved in calcium-dependent ubiquitination and subsequent proteasomal degradation of target proteins. Probably serves as a molecular bridge in ubiquitin E3 complexes. Participates in the ubiquitin-mediated degradation of beta-catenin (CTNNB1)."]
Component of a large E3 complex composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X; interacts directly with SIAH1, SIAH2 and SKP1.
[file:human/CACYBP/CACYBP-uniprot.txt "Component of some large E3 complex at least composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts directly with SIAH1, SIAH2 and SKP1."]
Siah1 is the central component of a multiprotein E3 ubiquitin ligase complex that targets beta-catenin for destruction in response to p53; the complex comprises Siah1, SIP, Skp1, and the F-box protein Ebi.
PMID:16085652
Structural basis: SIP engages Siah1 by an N-terminal dimerization domain and a consensus PXAXVXP motif; its C-terminal domain binds Skp1 and protrudes to form the scaffold bringing substrate and E2 into apposition.
PMID:16085652
Both the N-terminal dimerization element and the Siah-binding element are required for mediating beta-catenin destruction.
PMID:16085652

S100/calcyclin binding (calcium-dependent)

Homodimer; interacts with S100 family proteins S100A1, S100A6 (calcyclin), S100B, S100P, S100A12 in a calcium-dependent manner.
[file:human/CACYBP/CACYBP-uniprot.txt "Homodimer. Interacts with proteins of the S100 family S100A1, S100A6, S100B, S100P and S100A12 in a calcium-dependent manner"]
The name derives from binding to calcyclin (S100A6). High-throughput S100 interaction profiling (PMID:31837246) characterized S100 family PPIs quantitatively.

Localization

Nucleus and cytoplasm. Cytoplasmic at low calcium; upon retinoic acid induction and calcium increase in neuroblastoma cells, localizes to both nucleus and cytoplasm; nuclear fraction may be phosphorylated.
[file:human/CACYBP/CACYBP-uniprot.txt "Cytoplasmic at low calcium concentrations. In neuroblastoma cells, after a retinoic acid (RA) induction and calcium increase, it localizes in both the nucleus and cytoplasm."]

Homodimerization

X-ray crystallography and structural studies show SIP/CACYBP forms a homodimer via its N-terminal dimerization domain. PMID:16085652

High-throughput / contextual annotations (protein binding IPI)

PMID:25036637 (chaperone-cochaperone interaction network LUMIER) — generic high-throughput PPI.
PMID:31837246 (S100ome FP assay) — supports S100 protein binding specifically.
PMID:31980649 (EGFR network rewiring in CRC, membrane Y2H) — generic interactome.
PMID:33961781 (BioPlex dual proteome interactome) — generic high-throughput PPI.
PMID:36115835 (fragmentomics PDZ affinity mapping) — generic interactome.
These collapse to generic "protein binding" (GO:0005515) and are uninformative individually.

Exosome

PMID:20458337 (B-cell exosome proteome) — high-throughput MS localization; not a functional localization for a nucleocytoplasmic adaptor.

Orthology-transferred developmental/process terms (GO_REF:0000107, Ensembl Compara)

heart development, cardiac muscle cell differentiation, response to growth hormone, positive regulation of DNA replication, cellular response to calcium ion, nuclear envelope lumen, cell body, protein domain specific binding, tubulin binding. These are automatically transferred from orthologs and are not supported by direct human mechanistic evidence; mostly over-annotations relative to the core E3-adaptor role. Cellular response to calcium ion is consistent with the calcium-dependent S100 binding mechanism but remains a broad transferred term.

Assessment summary (core vs non-core)

CORE: SCF/Siah1 E3 ubiquitin ligase complex membership (part_of); molecular adaptor activity (bridge); ubiquitin protein ligase binding (Siah1/Siah2); S100 protein binding (calcium-dependent, basis of the protein's named function); protein homodimerization activity; beta-catenin destruction complex; nucleus/cytoplasm localization.
NON-CORE / contextual: heart development, cardiac muscle cell differentiation, response to growth hormone, positive regulation of DNA replication (orthology-transferred phenotypes); cellular response to calcium ion (broad).
OVER-ANNOTATED / uninformative: protein binding (GO:0005515) generic IPI x several; extracellular exosome; tubulin binding (InterPro IEA, no direct human evidence); protein domain specific binding; nuclear envelope lumen; cell body.

Falcon deep research findings (2026-06-07)

Synthesis of the Falcon (Edison) report, distinguishing CONFIRMS / NEW / PROVISIONAL relative to the existing review. PMIDs resolved via PubMed.

CONFIRMS (E3 adaptor / S100A6 / beta-catenin axis): Lee et al. 2008 NMR/ITC structure of the S100A6–SIP(189–219) complex confirms strictly Ca2+-dependent S100A6 binding to the C-terminal SGS region and frames SIP as a scaffold in an SCF-like (SCF-TBL1) E3 module linking Siah-1 (E2-recruiting) to Skp1–TBL1 (substrate-recruiting). Domain architecture: N-terminal helical-hairpin (M1–N78), central CS/p23-like (Y79–K177), C-terminal SGS (E178–F229) that folds upon S100A6 binding. [PMID:18803400 "the minimal S100A6 binding region in SIP was mapped to a 31-residue fragment (Ser189-Arg219)"; "a mode of binding to S100A6 that has not previously been observed"]. This complements the existing PMID:16085652 Siah1-assembly structure and our note that the complex is a non-cullin Siah1-based RING E3, not a canonical SCF.
NEW (S100A6 antagonizes the anti-beta-catenin/growth-suppressive function in gastric cancer): Ning et al. 2012 — overexpressed CacyBP/SIP inhibits MKN45 gastric cancer proliferation/tumorigenesis (in vitro + xenograft); a mutant lacking the S100-binding domain (ΔS100) suppresses growth even more strongly, and S100 binding negatively regulates this via beta-catenin protein level and Tcf/LEF transcription; effect is proteasome-dependent (MG132-reversible). PMID:22295074. Adds a regulatory logic (S100A6 = negative regulator) and a domain map consistent with our adaptor model. Does not change existing annotation actions.
NEW (SUMOylation at Lys16; cytoplasmic SUMO-conjugate): Wasik & Filipek 2013 — CacyBP/SIP binds the SUMO E2 Ubc9 and is SUMO1-modified; K16R abolishes modification; atypically, the SUMO-conjugated form is enriched in the cytoplasmic, not nuclear, fraction (in murine NB2a neuroblastoma cells). [PMID:24078263 "lysine 16 is the residue which undergoes sumoylation"; "sumoylated CacyBP/SIP is present in the cytoplasmic and not in the nuclear fraction"]. NEW PTM not previously in review; rodent cell system, so treat as a regulatory-mechanism lead, not a basis for a new human GO annotation.
PROVISIONAL / review-sourced (ERK1/2 phosphatase + PTM regulation): Filipek & Leśniak 2018 review and Wasik & Filipek 2013 report CacyBP/SIP phosphatase activity toward ERK1/2 (lowering Elk-1 phosphorylation), with activity tuned by PKC phosphorylation at Ser22/Thr23 and CKII phosphorylation at Thr184, and Ca2+/S100A6 inhibiting Thr184 phosphorylation. This is a potentially distinct molecular function (protein phosphatase / MAPK phosphatase activity) beyond the E3-adaptor role, but the primary phosphatase papers were NOT retrievable in this run and it is largely review-summarized — flag as PROVISIONAL; do NOT add a phosphatase GO annotation without primary verification. Recorded as a suggested question/experiment.
PROVISIONAL / review-sourced (stress, nucleolar NPM1 role, regulated translocation): Reviews state CacyBP/SIP relocalizes to perinuclear/nuclear compartments on Ca2+ increase, retinoic acid, or oxidative stress; protein levels rise ~40–50% under H2O2/radicicol; required to maintain NPM1 abundance and nucleolar integrity under oxidative stress (NB2a). Consistent with our accepted nuclear/cytoplasmic localization but adds a stress-response/nucleolar angle. PROVISIONAL (review-level, rodent system) — not used to alter annotations.
NEW context, low weight for GO (pan-cancer biomarker): Mo et al. 2024 — integrative TCGA/GTEx analysis (18,787 samples) finds CACYBP dysregulated across cancers (up in 14, down in 6), prognostic in 13, AUC>0.8 in 15/21 (overall AUC 0.95), with TMB/MSI/immune-infiltration associations and Western-blot validation in 6 paired LUAD. PMID:38322570. Bioinformatic/translational biomarker evidence; does not establish a mechanistic GO function and is not used to add annotations.

Attribution: PMIDs for Lee 2008 (PMID:18803400), Ning 2012 (PMID:22295074), Wasik 2013 (PMID:24078263), Mo 2024 (PMID:38322570) verified via PubMed (DOIs 10.1021/bi801233z, 10.1371/journal.pone.0030185, 10.1007/s11064-013-1155-4, 10.62347/OWVW7440).

Pn Notes

(CACYBP-pn-notes.md)

CACYBP PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9HB71
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/CACYBP/CACYBP-ai-review.yaml
AIGR review HTML: present - genes/human/CACYBP/CACYBP-ai-review.html
Gene notes: present - genes/human/CACYBP/CACYBP-notes.md
GOA TSV: present - genes/human/CACYBP/CACYBP-goa.tsv
UniProt record: present - genes/human/CACYBP/CACYBP-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/CACYBP.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/CACYBP.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/CACYBP/CACYBP-deep-research-falcon.md

AIGR Review Snapshot

Description: CACYBP (Calcyclin-Binding Protein; also known as SIP, Siah-Interacting Protein, and S100A6-binding protein) is a small nucleocytoplasmic adaptor protein that acts as a molecular bridge in a Siah1/Siah2-based, SKP1-containing E3 ubiquitin ligase complex. Through an N-terminal dimerization domain that binds Siah1 and a C-terminal domain that binds SKP1, it scaffolds substrate and the E2 enzyme into apposition, enabling ubiquitination and proteasomal degradation of target proteins, most notably beta-catenin (CTNNB1) in a p53-responsive pathway. CACYBP binds proteins of the S100 family (calcyclin/S100A6, S100A1, S100B, S100P, S100A12) in a calcium-dependent manner, linking calcium signaling to this ubiquitination machinery, and it forms homodimers. It is found in the cytoplasm at low calcium and redistributes between cytoplasm and nucleus upon calcium increase and certain stimuli.
Existing/core annotation action counts: ACCEPT: 11; KEEP_AS_NON_CORE: 1; MARK_AS_OVER_ANNOTATED: 18

PN Consistency Summary

Consistency: Major divergence. PN classifies CACYBP as an HSP90 cochaperone (CS/p23-like domain) and projects GO:0051879 Hsp90 protein binding. The review, the notes, and the Falcon deep research instead establish CACYBP/SIP as a Ca2+-regulated adaptor in a Siah1-based (non-cullin) E3 ubiquitin ligase that degrades beta-catenin, and as an S100A6/calcyclin-binding protein (PMID:16085652, 18803400, 22295074). The review has NO Hsp90-binding annotation and does not mention HSP90 cochaperone function. The CS/p23-like (HSP20-like, IPR007052/IPR037893) domain is the only basis for the HSP90-cochaperone call; CS-domain presence does not establish Hsp90 binding for this protein.
PN story / NEW pressure: PN asserts an Hsp90-cochaperone role NOT in existing GO annotations and NOT supported by the review/literature. GO:0051879 is a real term (verified) but is unsupported for CACYBP — the deep research found no primary Hsp90-binding data (the only Hsp90 link is review-level mention of radicicol-induced abundance changes, not binding). Conclusion: over-reaches — projecting Hsp90 binding onto CACYBP is a domain-similarity over-transfer. The protein's real shared MF is molecular adaptor activity (GO:0060090, already ACCEPT) and S100/ubiquitin-ligase binding.
Evidence alignment: PN cites no references. Review/deep-research PMIDs (16085652 Siah1 assembly; 18803400 S100A6 structure; 22295074 gastric-cancer beta-catenin) are entirely about E3-adaptor/S100 biology — zero overlap with any Hsp90-cochaperone literature.
Verdict: Domain-based misclassification — CACYBP is a Siah1 E3-ligase adaptor / S100A6-binding protein, not a demonstrated HSP90 cochaperone; Hsp90-binding projection is unsupported. Recommended edits: [MAP] remove/flag GO:0051879 projection onto Q9HB71 and reconsider the HSP90-cochaperone placement; the gene's shared MF is better represented by molecular adaptor activity (GO:0060090) / ubiquitin protein ligase binding, already in the review.

Full Consistency Review

UniProt: Q9HB71 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE
PN placement: Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone|CS domain containing ; PN-node mapping: cochaperone type → mapped/ok_for_propagation GO:0051879 Hsp90 protein binding (goa_status=more_specific_than_existing_goa); subtype/group/class/branch → no_mapping.
Consistency: Major divergence. PN classifies CACYBP as an HSP90 cochaperone (CS/p23-like domain) and projects GO:0051879 Hsp90 protein binding. The review, the notes, and the Falcon deep research instead establish CACYBP/SIP as a Ca2+-regulated adaptor in a Siah1-based (non-cullin) E3 ubiquitin ligase that degrades beta-catenin, and as an S100A6/calcyclin-binding protein (PMID:16085652, 18803400, 22295074). The review has NO Hsp90-binding annotation and does not mention HSP90 cochaperone function. The CS/p23-like (HSP20-like, IPR007052/IPR037893) domain is the only basis for the HSP90-cochaperone call; CS-domain presence does not establish Hsp90 binding for this protein.
PN story / NEW pressure: PN asserts an Hsp90-cochaperone role NOT in existing GO annotations and NOT supported by the review/literature. GO:0051879 is a real term (verified) but is unsupported for CACYBP — the deep research found no primary Hsp90-binding data (the only Hsp90 link is review-level mention of radicicol-induced abundance changes, not binding). Conclusion: over-reaches — projecting Hsp90 binding onto CACYBP is a domain-similarity over-transfer. The protein's real shared MF is molecular adaptor activity (GO:0060090, already ACCEPT) and S100/ubiquitin-ligase binding.
Mapping strategy: This gene argues the HSP90-cochaperone node should not project GO:0051879 onto CACYBP. CS-domain membership alone is too broad to assert Hsp90 binding (CS domains occur in non-Hsp90 contexts, as here). Treat as a node where this member is mis-bucketed.
Evidence alignment: PN cites no references. Review/deep-research PMIDs (16085652 Siah1 assembly; 18803400 S100A6 structure; 22295074 gastric-cancer beta-catenin) are entirely about E3-adaptor/S100 biology — zero overlap with any Hsp90-cochaperone literature.
Verdict: Domain-based misclassification — CACYBP is a Siah1 E3-ligase adaptor / S100A6-binding protein, not a demonstrated HSP90 cochaperone; Hsp90-binding projection is unsupported. Recommended edits: [MAP] remove/flag GO:0051879 projection onto Q9HB71 and reconsider the HSP90-cochaperone placement; the gene's shared MF is better represented by molecular adaptor activity (GO:0060090) / ubiquitin protein ligase binding, already in the review.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/CACYBP/CACYBP-ai-review.yaml
PN workbook rows: 1

PN row 1: Cytonuclear proteostasis | Chaperone | HSP90 system | HSP90 cochaperone | CS domain containing

UniProt: Q9HB71
In branches: CY
PN-node mapping records (path + ancestors):
- [subtype] Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone|CS domain containing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a family/domain/subtype label. It classifies PN members but is not itself a GO annotation target; any functional assertion should come from a parent role mapping or gene-specific review.
- [type] Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0051879 Hsp90 protein binding]
  rationale: This PN type groups HSP90 cochaperones. Hsp90 protein binding is the most defensible shared GO molecular-function target for propagation.
- [group] Cytonuclear proteostasis|Chaperone|HSP90 system
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [class] Cytonuclear proteostasis|Chaperone
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [branch] Cytonuclear proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

GO:0051879 Hsp90 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q9HB71
gene_symbol: CACYBP
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'CACYBP (Calcyclin-Binding Protein; also known as SIP, Siah-Interacting
  Protein, and S100A6-binding protein) is a small nucleocytoplasmic adaptor protein
  that acts as a molecular bridge in a Siah1/Siah2-based, SKP1-containing E3 ubiquitin
  ligase complex. Through an N-terminal dimerization domain that binds Siah1 and a
  C-terminal domain that binds SKP1, it scaffolds substrate and the E2 enzyme into
  apposition, enabling ubiquitination and proteasomal degradation of target proteins,
  most notably beta-catenin (CTNNB1) in a p53-responsive pathway. CACYBP binds proteins
  of the S100 family (calcyclin/S100A6, S100A1, S100B, S100P, S100A12) in a calcium-dependent
  manner, linking calcium signaling to this ubiquitination machinery, and it forms
  homodimers. It is found in the cytoplasm at low calcium and redistributes between
  cytoplasm and nucleus upon calcium increase and certain stimuli.'
alternative_products:
- name: '1'
  id: Q9HB71-1
- name: 2 (SIP-S, S)
  id: Q9HB71-2
  sequence_note: VSP_010171, VSP_010172
- name: '3'
  id: Q9HB71-3
  sequence_note: VSP_046862
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Nuclear localization is supported; CACYBP redistributes to the nucleus
      upon calcium increase and stimulation, consistent with its role in degradation
      of nuclear/cytoplasmic substrates.
    action: ACCEPT
    reason: CACYBP is documented in the nucleus and cytoplasm, with calcium-dependent
      nuclear redistribution.
    supported_by:
    - reference_id: file:human/CACYBP/CACYBP-uniprot.txt
      supporting_text: it localizes in both the nucleus and
        cytoplasm
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: The Siah1-SIP-Skp1-Ebi complex CACYBP participates in is a SIAH1 RING-finger
      E3 ligase, not a canonical SCF (SKP1-Cullin1-F-box) complex - it shares SKP1
      and an F-box subunit but lacks the defining cullin scaffold. The specific complex
      term GO:0030877 (beta-catenin destruction complex) is already accepted for this
      gene with IDA evidence, so the SCF complex assignment is a phylogenetic over-transfer
      from SKP1/F-box component sharing.
    action: MARK_AS_OVER_ANNOTATED
    reason: The Siah1-based E3 complex is non-cullin and therefore not an SCF complex
      as defined by GO:0019005, even though it shares SKP1 and an F-box subunit. The
      more specific GO:0030877 (beta-catenin destruction complex) annotation already
      captures the actual complex membership accurately.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: The E3
        complex comprises, in addition to Siah1, Siah-interacting protein (SIP), the
        adaptor protein Skp1, and the F-box protein Ebi
      reference_section_type: ABSTRACT
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: CACYBP binds the RING E3 ligases SIAH1/SIAH2 directly, a core molecular
      function underlying its bridging role.
    action: ACCEPT
    reason: Direct interaction of CACYBP/SIP with Siah1 is structurally characterized
      and is central to assembly of the beta-catenin-destruction E3 complex.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: SIP engages
        Siah1 by means of two elements
      reference_section_type: ABSTRACT
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: CACYBP serves as a molecular bridge/adaptor in ubiquitin E3 complexes,
      bringing substrate and E2 into apposition; this is its core molecular function.
    action: ACCEPT
    reason: CACYBP scaffolds Siah1 and Skp1 and provides the surface that brings substrate
      and the E2 enzyme together.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: this
        surface provides the scaffold for bringing substrate and the E2 enzyme into
        apposition in the functional complex
      reference_section_type: ABSTRACT
- term:
    id: GO:0007507
    label: heart development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Heart development is a broad developmental process not supported by direct
      mechanistic evidence for human CACYBP; the protein's documented role is as an
      E3 ligase adaptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: No direct evidence links CACYBP to heart development as a core function;
      this appears to be a phylogenetic/orthology-based broad transfer.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization is supported by direct subcellular localization data.
    action: ACCEPT
    reason: CACYBP localizes to the nucleus, especially after calcium increase.
    supported_by:
    - reference_id: file:human/CACYBP/CACYBP-uniprot.txt
      supporting_text: it localizes in both the nucleus and
        cytoplasm
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Cytoplasmic localization is well supported; CACYBP is cytoplasmic at low
      calcium concentrations.
    action: ACCEPT
    reason: Direct localization data place CACYBP in the cytoplasm.
    supported_by:
    - reference_id: file:human/CACYBP/CACYBP-uniprot.txt
      supporting_text: Cytoplasmic at low calcium
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0015631
    label: tubulin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Tubulin binding is an InterPro-based electronic inference without direct
      human experimental support; cytoskeletal roles are reported but not as a clear
      core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: No direct experimental evidence in the cached literature supports tubulin
      binding as a core CACYBP function; it is an automated domain-based transfer.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: CACYBP binds the E3 ligase Siah1 directly; core molecular function (consistent
      with the IBA annotation).
    action: ACCEPT
    reason: Direct Siah1 interaction is structurally established.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: SIP engages
        Siah1 by means of two elements
      reference_section_type: ABSTRACT
- term:
    id: GO:0044548
    label: S100 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Calcium-dependent binding to S100 family proteins (calcyclin/S100A6 and
      others) is the basis of the protein's name and a core molecular function linking
      calcium signaling to its ubiquitination machinery.
    action: ACCEPT
    reason: CACYBP interacts with multiple S100 proteins in a calcium-dependent manner.
    supported_by:
    - reference_id: file:human/CACYBP/CACYBP-uniprot.txt
      supporting_text: Interacts with proteins of the S100 family S100A1,
        S100A6, S100B, S100P and S100A12 in a calcium-dependent manner
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Generic protein binding from a high-throughput chaperone interaction (LUMIER)
      network; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding does not convey a specific CACYBP molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31837246
  qualifier: enables
  review:
    summary: The underlying data are S100 family interaction profiling, but the GO
      term used is generic protein binding; S100 protein binding is the informative
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; the specific S100 binding is captured
      by GO:0044548.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: Generic protein binding from an EGFR-network interactome study; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput screen does not identify a
      core CACYBP function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein binding from the BioPlex proteome-scale interactome; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is too general to represent CACYBP function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36115835
  qualifier: enables
  review:
    summary: Generic protein binding from a PDZ-affinity fragmentomics interactome;
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding does not convey a specific CACYBP molecular function.
- term:
    id: GO:0005641
    label: nuclear envelope lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Nuclear envelope lumen is an orthology-transferred localization with no
      direct support; inconsistent with the documented nucleoplasmic/cytoplasmic distribution.
    action: MARK_AS_OVER_ANNOTATED
    reason: An automated Ensembl Compara transfer not supported by direct human localization
      evidence.
- term:
    id: GO:0007507
    label: heart development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Heart development is a broad orthology-transferred process without direct
      mechanistic support for human CACYBP.
    action: MARK_AS_OVER_ANNOTATED
    reason: Automated transfer; CACYBP's core role is as an E3 ligase adaptor, not
      a defined cardiac developmental factor.
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: As for the IBA SCF complex annotation above, this is a non-cullin
      Siah1-based RING E3 ligase that shares SKP1/F-box subunits with SCF complexes
      but is not itself an SCF complex (no cullin scaffold). The specific
      GO:0030877 (beta-catenin destruction complex) is the accurate term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Same rationale as the IBA SCF annotation - the Siah1 E3 complex is non-cullin
      and therefore not an SCF complex as defined by GO:0019005.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: the
        adaptor protein Skp1, and the F-box protein Ebi
      reference_section_type: ABSTRACT
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Protein domain specific binding is a broad orthology-transferred molecular
      function without specific support; more informative terms (Siah1 binding, S100
      binding) are captured elsewhere.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general and automatically transferred; superseded by the specific binding
      terms.
- term:
    id: GO:0044297
    label: cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Cell body is an orthology-transferred neuronal localization without direct
      human support.
    action: MARK_AS_OVER_ANNOTATED
    reason: Automated Ensembl Compara transfer not supported by direct evidence for
      human CACYBP.
- term:
    id: GO:0045740
    label: positive regulation of DNA replication
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Positive regulation of DNA replication is a broad orthology-transferred
      process not supported by direct mechanistic evidence for human CACYBP.
    action: MARK_AS_OVER_ANNOTATED
    reason: Automated transfer; not a documented core function.
- term:
    id: GO:0055007
    label: cardiac muscle cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Cardiac muscle cell differentiation is an orthology-transferred developmental
      process without direct support for human CACYBP.
    action: MARK_AS_OVER_ANNOTATED
    reason: Automated transfer; not a documented core function.
- term:
    id: GO:0060416
    label: response to growth hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Response to growth hormone is an orthology-transferred process without
      direct mechanistic support for human CACYBP.
    action: MARK_AS_OVER_ANNOTATED
    reason: Automated transfer; not a documented core function.
- term:
    id: GO:0071277
    label: cellular response to calcium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Cellular response to calcium ion is consistent with CACYBP's calcium-dependent
      S100 binding and calcium-regulated localization, but the term is broad and the
      annotation is an orthology transfer.
    action: KEEP_AS_NON_CORE
    reason: The calcium-dependence of CACYBP function is real, but this broad process
      term is best retained as non-core relative to its E3-adaptor molecular role.
    supported_by:
    - reference_id: file:human/CACYBP/CACYBP-uniprot.txt
      supporting_text: in a calcium-dependent manner
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization is supported by direct immunofluorescence and
      the documented nuclear redistribution.
    action: ACCEPT
    reason: CACYBP localizes to the nucleus, consistent with nucleoplasmic detection.
    supported_by:
    - reference_id: file:human/CACYBP/CACYBP-uniprot.txt
      supporting_text: it localizes in both the nucleus and
        cytoplasm
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Cytosolic localization is well supported; CACYBP is cytoplasmic at low
      calcium.
    action: ACCEPT
    reason: Direct localization data place CACYBP in the cytosol.
    supported_by:
    - reference_id: file:human/CACYBP/CACYBP-uniprot.txt
      supporting_text: Cytoplasmic at low calcium
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: High-throughput exosome proteomics localization; not a functionally meaningful
      localization for a nucleocytoplasmic E3-adaptor protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mass-spectrometry co-purification hit without evidence for a functional
      extracellular/exosomal role.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16085652
  qualifier: enables
  review:
    summary: The underlying evidence is the specific CACYBP/SIP-Siah1 and CACYBP-Skp1
      interactions; the generic protein binding term is uninformative relative to those
      specific terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is too general; the informative interactions (Siah1/ubiquitin
      protein ligase binding, adaptor activity) are captured by other terms.
- term:
    id: GO:0030877
    label: beta-catenin destruction complex
  evidence_type: IDA
  original_reference_id: PMID:16085652
  qualifier: part_of
  review:
    summary: CACYBP/SIP is a component of the Siah1-based complex that targets beta-catenin
      for degradation; core function.
    action: ACCEPT
    reason: CACYBP is directly shown to be part of the multiprotein E3 complex that
      destroys beta-catenin in response to p53.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: a multiprotein E3 ubiquitin
        ligase complex that targets beta-catenin for destruction in response to p53
        activation
      reference_section_type: ABSTRACT
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:16085652
  qualifier: enables
  review:
    summary: CACYBP/SIP forms a homodimer via its N-terminal dimerization domain, which
      is required for Siah1 binding and beta-catenin destruction; core molecular property.
    action: ACCEPT
    reason: The N-terminal dimerization domain of SIP is structurally characterized
      and functionally required.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: An N-terminal dimerization domain of SIP sits
        across the saddle-shaped upper surface of Siah1
      reference_section_type: ABSTRACT
core_functions:
- description: Acts as a molecular adaptor/bridge that assembles a Siah1/Siah2-based,
    SKP1-containing E3 ubiquitin ligase complex, bringing substrate and the E2 enzyme
    into apposition to enable ubiquitination and proteasomal degradation of targets.
  supported_by:
  - reference_id: PMID:16085652
    supporting_text: this
      surface provides the scaffold for bringing substrate and the E2 enzyme into
      apposition in the functional complex
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  in_complex:
    id: GO:0030877
    label: beta-catenin destruction complex
- description: Binds the RING E3 ligase Siah1 (and Siah2) directly via an N-terminal
    dimerization domain and a Siah-binding motif, a core interaction for E3 complex
    assembly and beta-catenin degradation.
  supported_by:
  - reference_id: PMID:16085652
    supporting_text: SIP engages
      Siah1 by means of two elements
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
- description: Binds S100 family proteins (calcyclin/S100A6 and others) in a calcium-dependent
    manner, linking calcium signaling to the ubiquitination machinery.
  supported_by:
  - reference_id: file:human/CACYBP/CACYBP-uniprot.txt
    supporting_text: Interacts with proteins of the S100 family S100A1,
      S100A6, S100B, S100P and S100A12 in a calcium-dependent manner
    reference_section_type: DATABASE_ENTRY
  molecular_function:
    id: GO:0044548
    label: S100 protein binding
proposed_new_terms: []
suggested_questions:
- question: Which substrates beyond beta-catenin are degraded through the Siah1-CACYBP/SIP-SKP1
    E3 complex, and how does S100/calcium binding modulate substrate selection or
    complex assembly?
- question: Are the orthology-transferred developmental annotations (heart development,
    cardiac muscle cell differentiation) supported by any direct mechanistic role,
    or are they purely consequences of the E3-adaptor function in particular tissues?
- question: Does CACYBP/SIP have a bona fide protein phosphatase activity toward ERK1/2
    (and possibly p38/tau), as suggested by review-level reports, and is this activity
    regulated by PKC (Ser22/Thr23), CKII (Thr184), and Ca2+/S100A6 binding? This would
    represent a molecular function distinct from its E3-ligase adaptor role and needs
    primary biochemical confirmation.
- question: What is the functional consequence of SUMOylation at Lys16 (via Ubc9)
    for CACYBP/SIP, given the atypical cytoplasmic enrichment of the SUMO-conjugated
    form, and does it modulate E3-complex assembly, localization, or the proposed
    phosphatase activity?
suggested_experiments:
- description: Reconstitute the Siah1-CACYBP-Skp1-Ebi E3 complex in vitro and test
    whether calcium-loaded S100A6 binding to CACYBP enhances or inhibits beta-catenin
    ubiquitination, to define the calcium-to-ubiquitination coupling.
- description: Perform quantitative degradomics in CACYBP-knockout vs wild-type cells
    under calcium stimulation to identify the substrate repertoire dependent on CACYBP.
- description: Test for direct, purified-protein phosphatase activity of CACYBP/SIP
    toward phospho-ERK1/2 in vitro, and determine whether PKC/CKII phosphorylation
    or Ca2+/S100A6 binding modulate this activity, to confirm or refute the proposed
    ERK1/2 phosphatase function independent of the E3-adaptor role.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16085652
  title: Structural analysis of Siah1-Siah-interacting protein interactions and insights
    into the assembly of an E3 ligase multiprotein complex.
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:31837246
  title: High-throughput competitive fluorescence polarization assay reveals functional
    redundancy in the S100 protein family.
  findings: []
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing
    transforming levels of KRAS(G13D).
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:36115835
  title: Quantitative fragmentomics allow affinity mapping of interactomes.
  findings: []
- id: PMID:18803400
  title: 'Structure of the S100A6 complex with a fragment from the C-terminal domain
    of Siah-1 interacting protein: a novel mode for S100 protein target recognition.'
  full_text_unavailable: true
  findings:
  - statement: NMR/ITC structure of the Ca2+-loaded S100A6 complex with CACYBP/SIP(189-219)
      shows S100A6 binds the C-terminal SGS region of SIP in a strictly calcium-dependent
      manner, with a minimal binding fragment Ser189-Arg219; SIP is described as a
      scaffold in an SCF-like (SCF-TBL1) E3 ligase that links the Siah-1 module to
      the Skp1-TBL1 substrate-recruiting module.
- id: PMID:22295074
  title: S100A6 protein negatively regulates CacyBP/SIP-mediated inhibition of gastric
    cancer cell proliferation and tumorigenesis.
  full_text_unavailable: true
  findings:
  - statement: Overexpression of CacyBP/SIP inhibits gastric cancer cell proliferation
      and tumorigenesis, an effect strengthened by deleting the S100-binding domain;
      S100 binding negatively regulates this anti-proliferative activity through reduction
      of beta-catenin protein and Tcf/LEF transcriptional activity, and the beta-catenin
      reduction is proteasome-dependent (reversed by MG132).
- id: PMID:24078263
  title: The CacyBP/SIP protein is sumoylated in neuroblastoma NB2a cells.
  full_text_unavailable: true
  findings:
  - statement: CacyBP/SIP binds the SUMO E2 enzyme Ubc9 and is SUMO1-modified at Lysine
      16 (abolished by the K16R mutation); atypically, the SUMO-conjugated form is
      enriched in the cytoplasmic rather than the nuclear fraction.
- id: PMID:38322570
  title: Pan-analysis reveals CACYBP to be a novel prognostic and predictive marker
    for multiple cancers.
  full_text_unavailable: true
  findings:
  - statement: Integrative pan-cancer analysis reports CACYBP is differentially expressed
      across many cancer types (upregulated in 14, downregulated in 6), associated
      with prognosis in 13 cancers and with tumor mutational burden, microsatellite
      instability, and immune infiltration, with protein-level upregulation validated
      in paired lung adenocarcinoma specimens.

CACYBP

Gene Description

Existing Annotations Review

Core Functions

Acts as a molecular adaptor/bridge that assembles a Siah1/Siah2-based, SKP1-containing E3 ubiquitin ligase complex, bringing substrate and the E2 enzyme into apposition to enable ubiquitination and proteasomal degradation of targets.

Binds the RING E3 ligase Siah1 (and Siah2) directly via an N-terminal dimerization domain and a Siah-binding motif, a core interaction for E3 complex assembly and beta-catenin degradation.

Binds S100 family proteins (calcyclin/S100A6 and others) in a calcium-dependent manner, linking calcium signaling to the ubiquitination machinery.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human CACYBP (Calcyclin-binding protein; UniProt Q9HB71)

0) Target verification (mandatory)

1) Key concepts and current understanding (definitions + primary function)

1.1 What CACYBP is (conceptual definition)

1.2 Domain architecture (mechanistic definition)

1.3 Ca2+-dependent binding to S100A6 (calcyclin)

1.4 Ubiquitin–proteasome pathway: SCF-like E3 ligase module and β-catenin regulation

1.5 MAPK signaling: ERK1/2-associated phosphatase activity and regulation

1.6 Cytoskeleton interactions and cellular remodeling

2) Subcellular localization and where CACYBP acts in the cell

2.1 Basal localization and regulated translocation

2.2 SUMOylation and compartmentalization

2.3 Stress-related roles and nucleolar links

3) Recent developments (prioritizing 2023–2024)

3.1 2024 pan-cancer translational evidence: prognostic/predictive biomarker potential

3.2 2023 reviews on S100A6 biology integrate CACYBP as a central ligand/effector

3.3 2024 neurodegeneration/proteostasis framing (expert review)

4) Current applications and real-world implementations

4.1 Cancer biomarker research workflows

4.2 Mechanism-informed cancer biology (β-catenin axis)

4.3 Clinical trials and patents

5) Expert opinions and synthesis (authoritative perspectives)

6) Quantitative statistics and data highlights (recent + mechanistic)

7) Visual evidence (structural/domain mapping)

8) Summary for functional annotation (concise)

Key sources (URLs; publication dates)

Artifacts

Citations

📚 Additional Documentation

Notes

CACYBP (Calcyclin-Binding Protein / SIP / Siah-Interacting Protein) — research notes

Core molecular/cellular function: adaptor/bridge in a Siah1-based E3 ubiquitin ligase complex

S100/calcyclin binding (calcium-dependent)

Localization

Homodimerization

High-throughput / contextual annotations (protein binding IPI)

Exosome

Orthology-transferred developmental/process terms (GO_REF:0000107, Ensembl Compara)

Assessment summary (core vs non-core)

Falcon deep research findings (2026-06-07)

Pn Notes

CACYBP PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Cytonuclear proteostasis | Chaperone | HSP90 system | HSP90 cochaperone | CS domain containing

Projected GO annotations (1)

Note

📄 View Raw YAML