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.