NR3C4 androgen receptor genomic signaling in characterized jawed vertebrates

Full-length NR3C4 receptors couple androgen sensing to nuclear regulatory-DNA recognition and transcriptional responses in characterized jawed vertebrates. Cytosolic HSP90 and context-dependent co-chaperones support receptor competence. Nuclear availability, cooperative receptor-DNA assembly and coregulator recruitment are distinct aspects of the genomic response, not a universally ordered import switch. Mammalian FKBP4/FKBP5, p23, NCOA1/NCOA2 and NCOR1 provide experimentally grounded optional implementations. Fish paralogs differ in localization, ligand response and native physiological requirement. Steroid synthesis/transport, non-NR3C4 androgen sensors, non-genomic monomer signaling and ligand-binding-domain-deficient cancer variants lie outside this module.

MODULE:androgen_receptor_signalingDRAFTABSTRACTSignaling Pathwaymodules/androgen_receptor_signaling.yaml
androgen receptor signaling pathwayGO:0030521
PMID:39208923
Current structural synthesis supports domain cooperation and conformational plasticity rather than a single rigid receptor cycle.
PMID:19819965
Comparative phylogeny and receptor assays ground the jawed-vertebrate NR3C4 scope.
PMID:39227594
Non-genomic monomer activity is a demonstrated alternative mode, excluded from the genomic boundary rather than denied.
PMID:32449767
Coregulator abundance and context shape transcriptional outcomes.
PANTHER:PTN000163527
Retained legacy PTHR11528 PAINT provenance for ATP binding, ATP hydrolysis and folding. This is general HSP90 evidence, not proof of AR-specific signaling or cellular location.
PANTHER:PTN000163629
Retained legacy PTHR11528 PAINT provenance for cytosolic/complex roles and stabilization. Direct AR links are supported by the separately cited primary studies.
PANTHER:PTN002471265
Retained legacy FKBP PAINT provenance for PPIase and protein folding, present in PTHR10516/PTHR46512 caches. It does not establish the sign, target receptor or physiological requirement of regulation.

Independent manual literature and family/member audit. Fifteen audited gene exemplars are retained. The generated Falcon report is a discovery aid, not adjudicated evidence. Source caches remain untouched. Regulatory edges carry the positive or negative effect supported in the stated experimental context. These signs describe quantitative modulation and do not assert sufficient Boolean on/off gates. The file is a biological template, not a calibrated executable model.

12Nodes
5Parts
2Variant Sets
6Variants
10Annotons
12Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

  • androgen_receptor_signaling-deep-research-falcon.md (falcon)

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

21 gene-function check(s) reflected in core functions · 0 conflict(s) · 23 evidence or coverage gap(s) (44 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
hsp90_activity HSP90AA1 (Homo sapiens)
UniProtKB:P07900
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fkbp4_activity FKBP4 (Homo sapiens)
UniProtKB:Q02790
Family Representative 		heat shock protein binding in receptor co-chaperone complexes
GO:0031072 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fkbp4_activity Fkbp4 (Mus musculus)
UniProtKB:P30416
Family Representative 		heat shock protein binding in receptor co-chaperone complexes
GO:0031072 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fkbp5_activity FKBP5 (Homo sapiens)
UniProtKB:Q13451
Family Representative 		heat shock protein binding in receptor co-chaperone complexes
GO:0031072 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fkbp5_activity Fkbp5 (Mus musculus)
UniProtKB:Q64378
Family Representative 		heat shock protein binding in receptor co-chaperone complexes
GO:0031072 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
p23_activity PTGES3 (Homo sapiens)
UniProtKB:Q15185
Family Representative 		Hsp90 protein binding
GO:0051879 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_ligand_activity AR (Homo sapiens)
UniProtKB:P10275
Family Representative 		androgen binding
GO:0005497 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_ligand_activity Ar (Mus musculus)
UniProtKB:P19091
Family Representative 		androgen binding
GO:0005497 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_ligand_activity ara (Oryzias latipes)
UniProtKB:D1MV72
Family Representative 		androgen binding
GO:0005497 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
ar_ligand_activity arb (Oryzias latipes)
UniProtKB:D1MV73
Family Representative 		androgen binding
GO:0005497 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_ligand_activity AR (Chiloscyllium punctatum)
UniProtKB:D0VX34
Family Representative 		androgen binding
GO:0005497 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
ar_ligand_activity ar (Danio rerio)
UniProtKB:A4GT83
Family Representative 		androgen binding
GO:0005497 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_dna_activity AR (Homo sapiens)
UniProtKB:P10275
Family Representative 		sequence-specific DNA binding
GO:0043565 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_dna_activity Ar (Mus musculus)
UniProtKB:P19091
Family Representative 		sequence-specific DNA binding
GO:0043565 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_dna_activity ara (Oryzias latipes)
UniProtKB:D1MV72
Family Representative 		sequence-specific DNA binding
GO:0043565 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_dna_activity arb (Oryzias latipes)
UniProtKB:D1MV73
Family Representative 		sequence-specific DNA binding
GO:0043565 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_dna_activity AR (Chiloscyllium punctatum)
UniProtKB:D0VX34
Family Representative 		sequence-specific DNA binding
GO:0043565 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_dna_activity ar (Danio rerio)
UniProtKB:A4GT83
Family Representative 		sequence-specific DNA binding
GO:0043565 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ar_dna_activity:required_function AR (Homo sapiens)
UniProtKB:P10275
Family Representative 		androgen-responsive NR3C4 nuclear receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_dna_activity:required_function Ar (Mus musculus)
UniProtKB:P19091
Family Representative 		androgen-responsive NR3C4 nuclear receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_dna_activity:required_function ara (Oryzias latipes)
UniProtKB:D1MV72
Family Representative 		androgen-responsive NR3C4 nuclear receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_dna_activity:required_function arb (Oryzias latipes)
UniProtKB:D1MV73
Family Representative 		androgen-responsive NR3C4 nuclear receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_dna_activity:required_function AR (Chiloscyllium punctatum)
UniProtKB:D0VX34
Family Representative 		androgen-responsive NR3C4 nuclear receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_dna_activity:required_function ar (Danio rerio)
UniProtKB:A4GT83
Family Representative 		androgen-responsive NR3C4 nuclear receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ncoa1_activity NCOA1 (Homo sapiens)
UniProtKB:Q15788
Family Representative 		transcription coactivator activity
GO:0003713 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ncoa2_activity NCOA2 (Homo sapiens)
UniProtKB:Q15596
Family Representative 		transcription coactivator activity
GO:0003713 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ncor1_activity NCOR1 (Homo sapiens)
UniProtKB:O75376
Family Representative 		transcription corepressor activity
GO:0003714 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_transcription_activity AR (Homo sapiens)
UniProtKB:P10275
Family Representative 		nuclear steroid receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_transcription_activity Ar (Mus musculus)
UniProtKB:P19091
Family Representative 		nuclear steroid receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_transcription_activity ara (Oryzias latipes)
UniProtKB:D1MV72
Family Representative 		nuclear steroid receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_transcription_activity arb (Oryzias latipes)
UniProtKB:D1MV73
Family Representative 		nuclear steroid receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_transcription_activity AR (Chiloscyllium punctatum)
UniProtKB:D0VX34
Family Representative 		nuclear steroid receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ar_transcription_activity ar (Danio rerio)
UniProtKB:A4GT83
Family Representative 		nuclear steroid receptor activity
GO:0003707 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp90_activity cytosolic HSP90 chaperones participating in AR maturation
PANTHER:PTHR11528
Family 		ATP-dependent protein folding chaperone
GO:0140662 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11528.
fkbp4_activity FKBP52/FKBP4 co-chaperone orthologs
PANTHER:PTHR10516:SF25
Family 		heat shock protein binding in receptor co-chaperone complexes
GO:0031072 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10516:SF25.
fkbp5_activity FKBP51/FKBP5 co-chaperone orthologs
PANTHER:PTHR10516:SF26
Family 		heat shock protein binding in receptor co-chaperone complexes
GO:0031072 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10516:SF26.
p23_activity p23/PTGES3 HSP90 co-chaperones
PANTHER:PTHR22932:SF3
Family 		Hsp90 protein binding
GO:0051879 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR22932:SF3.
ar_ligand_activity NR3C4 androgen receptors, including teleost ara/arb paralogs
Family 		androgen binding
GO:0005497 		Family Id Missing
The family has no identifier linking it to a curated family review.
ar_dna_activity NR3C4 androgen receptors, including teleost ara/arb paralogs
Family 		sequence-specific DNA binding
GO:0043565 		Family Id Missing
The family has no identifier linking it to a curated family review.
ar_dna_activity:required_function NR3C4 androgen receptors, including teleost ara/arb paralogs
Family 		androgen-responsive NR3C4 nuclear receptor activity
GO:0003707 		Family Id Missing
The family has no identifier linking it to a curated family review.
ncoa1_activity NCOA1 coactivator subfamily
PANTHER:PTHR10684:SF1
Family 		transcription coactivator activity
GO:0003713 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10684:SF1.
ncoa2_activity NCOA2 coactivator subfamily
PANTHER:PTHR10684:SF2
Family 		transcription coactivator activity
GO:0003713 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10684:SF2.
ncor1_activity NCOR1 corepressor subfamily
PANTHER:PTHR13992:SF5
Family 		transcription corepressor activity
GO:0003714 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR13992:SF5.
ar_transcription_activity NR3C4 androgen receptors, including teleost ara/arb paralogs
Family 		nuclear steroid receptor activity
GO:0003707 		Family Id Missing
The family has no identifier linking it to a curated family review.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • ncor1_route ⊣ transcriptional_output [input]
    ncor1_route is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (15/15 grounded genes reviewed)

3 complete review(s) · 1 with deep research · 0 missing review · 14 reviewed but lacking deep research

Gene Review Complete Deep research
ar A4GT83 ✓ 33/37 ✗
AR D0VX34 ✓ ✓ ✗
AR P10275 ✓ 199/243 ✗
Ar P19091 ✓ 198/240 ✗
ara D1MV72 ✓ ✓ ✗
arb D1MV73 ✓ 21/29 ✗
Fkbp4 P30416 ✓ 45/57 ✗
FKBP4 Q02790 ✓ 68/69 ✗
FKBP5 Q13451 ✓ 47/48 ✗
Fkbp5 Q64378 ✓ 23/25 ✗
HSP90AA1 P07900 ✓ 506/522 ✗
NCOA1 Q15788 ✓ 80/124 ✗
NCOA2 Q15596 ✓ 52/72 ✗
NCOR1 O75376 ✓ 81/110 ✗
PTGES3 Q15185 ✓ ✓ ✓

Details

Context
GnathostomataNCBITaxon:7776
cytosolGO:0005829 nucleusGO:0005634
PMID:19819965
Phylogenetic and functional comparison places characterized NR3C4 receptors before the cartilaginous/bony-fish split and distinguishes teleost duplication.
PMID:36918573
Native medaka paralog functions demonstrate limits on transferring mammalian physiology.
NR3C4 androgen-responsive genomic signalingSignaling Pathwayandrogen_receptor_signaling

A taxon-bounded genomic receptor template with contextual mammalian co-chaperone and coregulator implementations. Connections describe material or regulatory contributions, not sufficient Boolean switches or an invariant temporal ordering.

androgen receptor signaling pathwayGO:0030521
Context
GnathostomataNCBITaxon:7776
cytosolGO:0005829 nucleusGO:0005634
PMID:19819965
Phylogenetic and functional comparison places characterized NR3C4 receptors before the cartilaginous/bony-fish split and distinguishes teleost duplication.
PMID:36918573
Native medaka paralog functions demonstrate limits on transferring mammalian physiology.

All 15 unique exemplars have gene reviews. Human and mouse FKBP identities are retained separately; optional cofactor implementations are not interchangeable physiological requirements. A supported mammalian-like N/C interaction motif is not demanded of shark AR. HSP70/HOP, nuclear import/export machinery, other chromatin factors and ligand metabolism are acknowledged background machinery outside the named-member boundary. PANTHER and PAINT evidence supports membership/general molecular functions, not automatic assignment of every family member to AR signaling.

Connections

receptor_competence -> ligand_response Provides Input For
The chaperone machinery supplies a ligand-responsive receptor pool; this is not a claim that isolated receptor-domain ligand binding always requires chaperones.
PMID:20048054
Co-chaperone/HSP90 assembly changes the number of androgen-binding competent AR molecules in the tested cells.
Androgen-dependent receptor conformations support the genomic route. Nuclear availability can be regulated without a universal cytoplasm-to-nucleus switch or a fixed order of dimerization and import. Receptor activation alone is not sufficient without DNA-binding competence.
PMID:19819965
The cloned shark receptor combines androgen-responsive localization and ARE reporter activity.
PMID:27959439
Testosterone-responsive mouse AR directly occupies and activates the Aard promoter.
PMID:19574395
Nuclear AR with a damaged DBD fails genomic function.
PMID:26507457
Medaka paralogs differ in subcellular localization and ligand-responsive activity.
The receptor and its regulatory DNA context provide sites for cofactor recruitment; cofactors can also associate before DNA binding, so this is a functional connection rather than a strict temporal sequence.
PMID:10567563
SRC1 interacts with AR activation domains.
PMID:9717843
AR-TIF2 functional interaction depends on the promoter and receptor domains.
PMID:17505061
Antagonist-bound AR recruits corepressor components at responsive promoters.
Productive receptor-DNA engagement connects ligand sensing to the genomic transcriptional response, together with activation-domain and cellular transcription machinery context.
PMID:27959439
ChIP/EMSA and reporter assays connect promoter-bound AR to Aard transcription.
PMID:19574395
DNA-binding-domain disruption uncouples nuclear AR from genomic function.
fkbp4_route -> nuclear_dna_engagement Positively Regulates
In tested human prostate cancer cells, FKBP52 supports AR dimerization and chromatin association. This does not mean it is required for AR import in mouse tissues or every vertebrate.
Context
Homo sapiensNCBITaxon:9606
tested human prostate cancer cell systems
PMID:34057812
FKBP52 depletion reduces AR dimerization/chromatin binding while preserving nuclear translocation.
PMID:17142810
Mouse Fkbp4 knockout preserves AR ligand binding and nuclear entry.
fkbp5_route -> ligand_response Positively Regulates
Human FKBP51 can increase the androgen-binding competent AR pool through HSP90/p23 assembly. Its inhibitory effect on GR must not be transferred as a universal negative AR edge.
Context
Homo sapiensNCBITaxon:9606
tested prostate cancer cell and xenograft systems
PMID:20048054
FKBP51 promotes HSP90/p23 complex assembly and increases AR molecules undergoing androgen binding.
fkbp5_route -> nuclear_dna_engagement Positively Regulates
Human FKBP51 can support AR dimerization and chromatin binding without being an obligatory nuclear-import factor or a universal reproductive requirement.
Context
Homo sapiensNCBITaxon:9606
tested human prostate cancer cell systems
PMID:34057812
FKBP51 depletion impairs AR dimer formation and chromatin binding.
PMID:17142810
Fkbp5-null mouse males lack the tested AR-dependent reproductive defects seen after Fkbp4 loss.
p23_route -> ligand_response Positively Regulates
p23 can enhance AR ligand-binding competence; some effects survive loss of p23-HSP90 binding, so its contribution is not represented solely as ATPase-cycle regulation.
Context
Homo sapiensNCBITaxon:9606
PMID:22899854
p23 increases ligand-binding capacity and retains some AR potentiation when HSP90 binding is disrupted.
p23_route -> nuclear_dna_engagement Positively Regulates
p23 supports AR protein stability and occupancy/function at target genes in tested human cancer models.
Context
Homo sapiensNCBITaxon:9606
tested prostate cancer models
PMID:22899854
p23 enhances AR occupancy at target promoters.
PMID:41193657
PTGES3 directly binds AR, regulates protein stability and supports nuclear target-gene function.
ncoa1_route -> transcriptional_output Positively Regulates
SRC1 provides a positive coactivation contribution in the tested promoter contexts. It is not a ligand-independent substitute for AR or a universally required SRC paralog.
Context
Homo sapiensNCBITaxon:9606
PMID:10567563
SRC1 recruitment via AR activation domains supports transcriptional potentiation.
ncoa2_route -> transcriptional_output Positively Regulates
TIF2 provides a positive coactivation contribution in the tested human AR systems, with promoter and cell-context dependence.
Context
Homo sapiensNCBITaxon:9606
PMID:9717843
TIF2 potentiation is stronger on the complex MMTV promoter than on GRE-TATA.
PMID:17079484
TIF2 depletion reduces expression of AR-induced genes.
ncor1_route -> transcriptional_output Negatively Regulates
NCOR1 supplies a repressive regulatory contribution at selected AR-responsive promoters. This is not a general prohibition of all AR signaling whenever NCOR1 is present.
Context
Homo sapiensNCBITaxon:9606
antagonist-bound AR or FBI-1-enhanced corepressor recruitment
PMID:17505061
Antagonist-bound AR recruits corepressor components.
PMID:20812024
FBI-1 promotes NCoR recruitment and repression in specific prostate cancer contexts.
Part 1: receptor competence
Receptor maturation and context-dependent co-chaperonesRegulatory Stepreceptor_competence

Cytosolic HSP90 supports full-length receptor competence. The named FKBP and p23 implementations are optional choices in this cross-taxon template; optional does not mean dispensable in every assayed cell. GR maturation structures or immunophilin-exchange/import experiments are comparative evidence and are not direct proof of an identical AR complex.

Annotons

ATP-dependent HSP90 client maturation
hsp90_activity
Participant: Family: cytosolic HSP90 chaperones participating in AR maturation
Family:
cytosolic HSP90 chaperones participating in AR maturationPANTHER:PTHR11528 The parent family also contains proteins with other cellular/client roles. The cytosolic AR-client constraint is required; family membership alone does not assign this pathway.
Representative Members: HSP90AA1 (Homo sapiens)UniProtKB:P07900
Required Function:
cytosolic ATP-dependent chaperoning of full-length NR3C4 receptorsGO:0140662 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

ATP-dependent protein folding chaperoneGO:0140662

Locations

cytosolGO:0005829

Maintains a receptor pool competent for ligand response through the co-chaperone-regulated ATPase cycle. This represents client maturation, not an invariant requirement for every assay of an isolated receptor domain.

PMID:20048054
Recombinant HSP90/co-chaperone assembly and cellular AR assays connect the chaperone complex to androgen-binding competence.
file:human/HSP90AA1/HSP90AA1-ai-review.yaml
The target review independently supports the HSP90AA1 ATP-dependent chaperone function while distinguishing it from isoform-unspecific AR evidence.
Variant set: Selected mammalian co-chaperone contributions by co-chaperone identity and cell context (Zero Or More)
PMID:17142810
Mouse genetics distinguishes FKBP52 requirement from FKBP51 dispensability in the tested reproductive traits.
PMID:34057812
Human prostate cancer cells display positive AR effects of both FKBPs.
FKBP4-associated receptor regulationRegulatory Stepfkbp4_route

A selected mammalian implementation, not a required step in every jawed-vertebrate AR response.

Context
Homo sapiensNCBITaxon:9606 Mus musculusNCBITaxon:10090

The named implementations are experimentally grounded in these mammals; the whole vertebrate clade is not assigned their exact native requirement.

Annotons

FKBP52 context-dependent co-chaperone activity
fkbp4_activity
Participant: Family: FKBP52/FKBP4 co-chaperone orthologs
Family:
FKBP52/FKBP4 co-chaperone orthologsPANTHER:PTHR10516:SF25 PANTHER19.0 places the human and mouse exemplars in this subfamily; current UniProt places them in shared PTHR46512:SF9 (PEPTIDYLPROLYL ISOMERASE). Both placements are supported. The release subfamily preserves FKBP4/FKBP5 identity without claiming identical effects across steroid receptors.
Representative Members: FKBP4 (Homo sapiens)UniProtKB:Q02790 Fkbp4 (Mus musculus)UniProtKB:P30416
Required Function:
HSP90-associated modulation of NR3C4 receptor complexesGO:0031072 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

heat shock protein binding in receptor co-chaperone complexesGO:0031072 This shared family role uses the broader heat-shock-protein-binding capability because mouse complex-association evidence does not independently resolve every binary contact. Human gene reviews retain the more specific HSP90-binding refinement where directly supported.

Locations

cytosolGO:0005829

A co-chaperone role with receptor- and context-dependent effects. PPIase activity is independently established but its catalytic requirement is not assumed for every AR response.

PMID:34057812
Depletion of either FKBP51 or FKBP52 reduces AR dimerization and chromatin binding in human prostate cancer cells without blocking nuclear translocation.
PMID:17142810
Native mouse knockouts establish distinct reproductive requirements for Fkbp4 and Fkbp5; loss of Fkbp4 does not abolish AR hormone binding or nuclear entry.

The shared molecular-function level follows both mammalian gene reviews. Human HSP90 binding is more specifically supported; mouse evidence establishes HSP90/receptor-complex association without independently resolving every binary contact.

FKBP5-associated receptor regulationRegulatory Stepfkbp5_route

A selected mammalian implementation, not a required step in every jawed-vertebrate AR response.

Context
Homo sapiensNCBITaxon:9606 Mus musculusNCBITaxon:10090

The named implementations are experimentally grounded in these mammals; the whole vertebrate clade is not assigned their exact native requirement.

Annotons

FKBP51 context-dependent co-chaperone activity
fkbp5_activity
Participant: Family: FKBP51/FKBP5 co-chaperone orthologs
Family:
FKBP51/FKBP5 co-chaperone orthologsPANTHER:PTHR10516:SF26 PANTHER19.0 places the human and mouse exemplars in this subfamily; current UniProt places them in shared PTHR46512:SF9 (PEPTIDYLPROLYL ISOMERASE). Both placements are supported. The release subfamily preserves FKBP4/FKBP5 identity without claiming identical effects across steroid receptors.
Representative Members: FKBP5 (Homo sapiens)UniProtKB:Q13451 Fkbp5 (Mus musculus)UniProtKB:Q64378
Required Function:
HSP90-associated modulation of NR3C4 receptor complexesGO:0031072 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

heat shock protein binding in receptor co-chaperone complexesGO:0031072 This shared family role uses the broader heat-shock-protein-binding capability because mouse complex-association evidence does not independently resolve every binary contact. Human gene reviews retain the more specific HSP90-binding refinement where directly supported.

Locations

cytosolGO:0005829

A co-chaperone role with receptor- and context-dependent effects. PPIase activity is independently established but its catalytic requirement is not assumed for every AR response.

PMID:34057812
Depletion of either FKBP51 or FKBP52 reduces AR dimerization and chromatin binding in human prostate cancer cells without blocking nuclear translocation.
PMID:17142810
Native mouse knockouts establish distinct reproductive requirements for Fkbp4 and Fkbp5; loss of Fkbp4 does not abolish AR hormone binding or nuclear entry.
PMID:20048054
FKBP51 promotes p23 recruitment to ATP-bound HSP90 and increases androgen-binding competent AR in prostate cancer models.

The shared molecular-function level follows both mammalian gene reviews. Human HSP90 binding is more specifically supported; mouse evidence establishes HSP90/receptor-complex association without independently resolving every binary contact.

p23/PTGES3-associated receptor regulationRegulatory Stepp23_route
Context
Homo sapiensNCBITaxon:9606

Direct target mechanism is supported in the stated human receptor/cell systems; universal cofactor necessity is not inferred.

Annotons

p23-mediated receptor maturation and stabilization
p23_activity
Participant: Family: p23/PTGES3 HSP90 co-chaperones
Family:
p23/PTGES3 HSP90 co-chaperonesPANTHER:PTHR22932:SF3
Representative Members: PTGES3 (Homo sapiens)UniProtKB:Q15185
Required Function:
p23-mediated regulation of AR maturation or stabilityGO:0051879 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

Hsp90 protein bindingGO:0051879

Locations

cytosolGO:0005829 nucleusGO:0005634

p23 binds ATP-bound HSP90 and also supports AR through partly HSP90-independent interactions. The binding MF captures the co-chaperone aspect; it does not assert that all AR effects require HSP90 binding.

PMID:10543959
p23 binds ATP-bound HSP90 and also has independent anti-aggregation activity.
PMID:22899854
Human p23 increases AR ligand-binding capacity and promoter occupancy; an HSP90-binding-defective mutant retains some AR potentiation.
PMID:41193657
Human prostate cancer experiments establish direct PTGES3-AR binding, AR protein stabilization and nuclear target-gene function.
Part 2: androgen sensing
Androgen sensing and receptor conformational responseRegulatory Stepligand_response

Ligand recognition changes receptor conformation and regulatory interactions. This node is restricted to the full-length ligand-responsive route; constitutively active LBD-deficient variants, pharmacological promiscuity and other androgen sensors are outside its scope.

Annotons

Ligand-responsive NR3C4 receptor
ar_ligand_activity
Participant: Family: NR3C4 androgen receptors, including teleost ara/arb paralogs
Family:
NR3C4 androgen receptors, including teleost ara/arb paralogs PANTHER PTHR48092 contains these accessions but is a broader nuclear-receptor grouping with official name KNIRPS-RELATED PROTEIN-RELATED. No PANTHER ID is asserted to mean NR3C4 itself. The free family intent, curated accessions and comparative phylogeny define this selector.
Representative Members: AR (Homo sapiens)UniProtKB:P10275 Ar (Mus musculus)UniProtKB:P19091 ara (Oryzias latipes)UniProtKB:D1MV72 arb (Oryzias latipes)UniProtKB:D1MV73 AR (Chiloscyllium punctatum)UniProtKB:D0VX34 ar (Danio rerio)UniProtKB:A4GT83
Required Function:
androgen binding by NR3C4 receptorsGO:0005497 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

androgen bindingGO:0005497 This annoton represents ligand recognition; the separate transcription annoton represents nuclear steroid receptor activity.

Locations

cytosolGO:0005829 nucleusGO:0005634

Full-length receptors bind and respond to androgens. Testosterone, dihydrotestosterone and fish 11-ketotestosterone are experimentally relevant in different receptor/taxon contexts; they are not asserted as an identical ligand set or potency ranking for every exemplar.

PMID:3353726
The cloned human receptor binds androgens specifically with high affinity.
PMID:18469035
The cloned zebrafish receptor supports androgen binding and transactivation, including testosterone and 11-ketotestosterone.
PMID:19819965
The cloned shark receptor responds to classical androgens in an ARE reporter assay; conserved ligand-contact residues and receptor-dependent responses support inferred androgen binding, rather than a direct affinity measurement.
PMID:26507457
Medaka ara and arb encode functional androgen-responsive receptors with different transactivation and localization properties. Ligand binding is inferred from receptor/domain evidence here; direct binding is separately measured for the zebrafish exemplar.
Part 3: nuclear DNA engagement
Nuclear availability and response-element engagementRegulatory Stepnuclear_dna_engagement

The genomic route requires nuclear access, which may involve ligand-dependent redistribution or a pre-existing nuclear receptor pool. No obligatory FKBP51-to-FKBP52 exchange/import switch is asserted. DNA-directed receptor assemblies include dimers and higher-order states; non-genomic monomer signaling is excluded rather than denied.

Annotons

NR3C4 response-element recognition
ar_dna_activity
Participant: Family: NR3C4 androgen receptors, including teleost ara/arb paralogs
Family:
NR3C4 androgen receptors, including teleost ara/arb paralogs
Representative Members: AR (Homo sapiens)UniProtKB:P10275 Ar (Mus musculus)UniProtKB:P19091 ara (Oryzias latipes)UniProtKB:D1MV72 arb (Oryzias latipes)UniProtKB:D1MV73 AR (Chiloscyllium punctatum)UniProtKB:D0VX34 ar (Danio rerio)UniProtKB:A4GT83
Required Function:
androgen-responsive NR3C4 nuclear receptor activityGO:0003707 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

sequence-specific DNA bindingGO:0043565

Locations

nucleusGO:0005634 chromatinGO:0000785

The receptor DNA-binding domain recognizes regulatory DNA, commonly as a cooperative head-to-head dimer at paired ARE half-sites. Nuclear accumulation, oligomerization and DNA occupancy are distinct measurements; this grouping does not impose a universal temporal order or make nuclear localization sufficient for transcription.

PMID:38604378
Human AR DBD structures and binding assays demonstrate cooperative binding at natural AREs in head-to-head dimer conformations.
PMID:27959439
Mouse Sertoli-cell ChIP, EMSA and reporter assays connect ligand-bound AR to the Aard promoter.
PMID:19574395
Mouse Sertoli-cell AR lacking its second zinc finger remains nuclear but loses genomic function.
PMID:36918573
Native medaka localization varies by paralog and tissue; transfected-cell localization does not define all native tissues.
Part 4: selected coregulator implementations (optional)
Context-dependent coregulator recruitmentRegulatory Stepcoregulator_selection

NCOA1, NCOA2 and NCOR1 are selected mammalian implementations, not consecutive enzymes or obligatory components of one invariant complex. Other coactivators and chromatin regulators are outside the named-member panel. Recruitment through AF1, AF2 and partner-mediated contacts depends on receptor construct, ligand, promoter and cell context.

Variant set: Coactivation and corepression implementations by coregulator and promoter context (Zero Or More)
PMID:32449767
Coregulator functions and compensation are context-dependent; names do not impose a universal direction in all receptor systems.
PMID:10567563
SRC1 AF1 recruitment can remain functional when its LXXLL motifs are disrupted.
PMID:15563469
AR-LBD structures demonstrate recognition of FXXLF and selected SRC LXXLL motifs, complementing full-length AF1 recruitment experiments.
NCOA1 coactivationRegulatory Stepncoa1_route
Context
Homo sapiensNCBITaxon:9606

Direct target mechanism is supported in the stated human receptor/cell systems; universal cofactor necessity is not inferred.

Annotons

NCOA1 contextual coactivation
ncoa1_activity
Participant: Family: NCOA1 coactivator subfamily
Family:
NCOA1 coactivator subfamilyPANTHER:PTHR10684:SF1
Representative Members: NCOA1 (Homo sapiens)UniProtKB:Q15788
Required Function:
AR-associated transcription coactivator activityGO:0003713 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

transcription coactivator activityGO:0003713

Locations

nucleusGO:0005634

SRC1 can contact AR AF1 through its glutamine-rich region as well as AF2 through LXXLL motifs. LXXLL mutations retain potentiation in the tested full-length AR system; this is not a universal AF1-only rule.

PMID:10567563
SRC1 interacts with the AR N terminus through a conserved glutamine-rich region and with the ligand-binding domain through LXXLL motifs. In the tested constructs, an SRC1 mutant lacking functional LXXLL motifs retains AR potentiation.
PMID:10454556
Target-specific experiments support coactivation with construct, promoter and cell-context limits.
NCOA2 coactivationRegulatory Stepncoa2_route
Context
Homo sapiensNCBITaxon:9606

Direct target mechanism is supported in the stated human receptor/cell systems; universal cofactor necessity is not inferred.

Annotons

NCOA2 contextual coactivation
ncoa2_activity
Participant: Family: NCOA2 coactivator subfamily
Family:
NCOA2 coactivator subfamilyPANTHER:PTHR10684:SF2
Representative Members: NCOA2 (Homo sapiens)UniProtKB:Q15596
Required Function:
AR-associated transcription coactivator activityGO:0003713 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

transcription coactivator activityGO:0003713

Locations

nucleusGO:0005634

TIF2/SRC2 enhances human AR transactivation in promoter-dependent assays and supports AR-induced genes in prostate cancer cells. AF2 constructs demonstrate one recruitment mode, not the only route used by full-length AR.

PMID:9717843
In human AR construct assays in CHO cells and yeast, TIF2 potentiation depends on the AR AF2 core and promoter context; the MMTV promoter responds more strongly than the minimal GRE-TATA promoter.
PMID:17079484
TIF2 depletion reduces AR-induced target-gene expression and slows proliferation in the tested prostate cancer cell lines.
NCOR1 repressionRegulatory Stepncor1_route
Context
Homo sapiensNCBITaxon:9606

Direct target mechanism is supported in the stated human receptor/cell systems; universal cofactor necessity is not inferred.

Annotons

NCOR1 contextual corepression
ncor1_activity
Participant: Family: NCOR1 corepressor subfamily
Family:
NCOR1 corepressor subfamilyPANTHER:PTHR13992:SF5
Representative Members: NCOR1 (Homo sapiens)UniProtKB:O75376
Required Function:
context-dependent AR-associated transcription corepressor activityGO:0003714 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

transcription corepressor activityGO:0003714

Locations

nucleusGO:0005634

Recruited corepressor complexes can reduce AR-dependent target-gene transcription. Antagonist-bound AR and FBI-1-dependent promoter recruitment are tested contexts; these data do not require NCOR1 in every liganded receptor assembly or imply NCOR1 supplies deacetylase catalysis.

PMID:17505061
Antagonist-bound AR recruits SIRT1 and nuclear receptor corepressor to responsive promoters.
PMID:20812024
FBI-1 enhances NCoR/SMRT recruitment at endogenous PSA regulatory sequences.
PMID:11931768
NCOR1 scaffolds and activates an HDAC3-containing corepressor complex; HDAC3 supplies deacetylase catalysis.
Part 5: genomic transcriptional response
AR-dependent transcriptional responseRegulatory Steptranscriptional_output

Transcription is the endpoint of this genomic module. Germline sex determination, spermatogenesis, growth, behavior and cancer phenotypes are downstream, tissue-specific consequences and are not universal module outputs.

Annotons

DNA-directed NR3C4 transcriptional regulation
ar_transcription_activity
Participant: Family: NR3C4 androgen receptors, including teleost ara/arb paralogs
Family:
NR3C4 androgen receptors, including teleost ara/arb paralogs
Representative Members: AR (Homo sapiens)UniProtKB:P10275 Ar (Mus musculus)UniProtKB:P19091 ara (Oryzias latipes)UniProtKB:D1MV72 arb (Oryzias latipes)UniProtKB:D1MV73 AR (Chiloscyllium punctatum)UniProtKB:D0VX34 ar (Danio rerio)UniProtKB:A4GT83
Required Function:
androgen-responsive NR3C4 nuclear receptor activityGO:0003707 The GO term supplies the general molecular capability. The stated family identity and AR-specific contextual role further constrain this module selection.

Function

nuclear steroid receptor activityGO:0003707

Processes

androgen receptor signaling pathwayGO:0030521

Locations

nucleusGO:0005634 chromatinGO:0000785

DNA-bound AR regulates RNA-polymerase-II target genes through receptor activation domains and context-specific regulatory partners. Different genes can be induced or repressed, and tissue outputs are not interchangeable across species.

PMID:27959439
Native mouse receptor activity is connected to direct target promoter binding and transcription.
PMID:10567563
AR-domain/SRC1 perturbations connect recruitment interfaces to reporter transcription.
PMID:17079484
NCOA2 depletion changes AR-induced target-gene expression in human prostate cancer cells.
PMID:36918573
Native medaka mutants demonstrate lineage- and paralog-dependent behavioral and morphological outcomes, without the same sperm requirement as mammalian Sertoli-cell AR.