# NCOA2

**NCOA2** (nuclear receptor coactivator 2), also known as SRC-2, TIF2, or GRIP1, is a human protein-coding gene on chromosome 8q13.3 that encodes a transcriptional coactivator for nuclear hormone receptors, including steroid, thyroid, retinoid, and vitamin D receptors.<sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup><sup> • </sup><sup>[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669)</sup> The protein acts as an intermediary factor for the ligand-dependent activity of these receptors, which regulate their target genes upon binding of cognate response elements.<sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup> The gene is also a recurring fusion partner in several cancers, including acute myeloid leukemia, acute lymphoblastic leukemia, mesenchymal chondrosarcoma, and spindle-cell rhabdomyosarcoma.<sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup><sup> • </sup><sup>[3](https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1570070/pdf)</sup>

| Key fact | Detail |
|---|---|
| Official name | Nuclear receptor coactivator 2; HGNC:7669, Entrez Gene ID 10499, OMIM 601993, UniProt Q15596<sup>[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669)</sup><sup> • </sup><sup>[4](https://www.genecards.org/card/NCOA2)</sup> |
| Location | Chromosome 8q13.3; GRCh38 chr8:70,109,782–70,456,446 (minus strand); 35 exons<sup>[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669)</sup><sup> • </sup><sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup> |
| Protein | 1,464 amino acids, molecular mass 159,157 Da; a p160-family coactivator with bHLH-PAS, nuclear receptor interaction, and two C-terminal activation domains<sup>[4](https://www.genecards.org/card/NCOA2)</sup><sup> • </sup><sup>[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7351129/)</sup> |
| Main aliases | SRC-2, TIF2, GRIP1, NCoA-2, KAT13C, bHLHe75<sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup> |
| Cancer fusions | KAT6A-NCOA2 in acute myeloid leukemia, ETV6-NCOA2 in acute lymphoblastic leukemia, HEY1-NCOA2 in mesenchymal chondrosarcoma<sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup> |
| Prostate cancer | Amplified or overexpressed in 8% of primary tumors and 37% of metastatic prostate cancers<sup>[6](https://www.jci.org/articles/view/76412)</sup> |
| Loss-of-function constraint | gnomAD pLI of 1 and LOEUF of 0.21, indicating strong intolerance of loss-of-function variation<sup>[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669)</sup> |

## Function and mechanism

NCOA2 is a member of the p160 steroid receptor coactivator (SRC) family, together with [NCOA1](https://www.edgepedia.org/ncoa1) (SRC-1) and [NCOA3](https://www.edgepedia.org/ncoa3) (SRC-3); the three proteins share similar amino acid sequences, domain architecture, and a molecular weight of about 160 kDa.<sup>[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7351129/)</sup> The protein does not bind DNA directly. Instead, it is recruited to enhancer or promoter regions of target genes through interaction with transcription factors, where it modulates transcription.<sup>[6](https://www.jci.org/articles/view/76412)</sup>

Receptor engagement and activation domains define the coactivator's mechanism. NCOA2 engages agonist-bound receptor ligand-binding domains through three LxxLL NR-box motifs in a receptor-interaction domain that becomes structured upon receptor engagement. Its AD1 region transactivates by recruiting the histone acetyltransferases CBP and p300, while AD2 acts independently and binds the histone methyltransferases [CARM1](https://www.edgepedia.org/carm1) and PRMT1.<sup>[7](https://affinage.wi.mit.edu/gene/NCOA2)</sup><sup> • </sup><sup>[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)</sup> The N-terminal basic helix-loop-helix-[PAS domain](https://www.edgepedia.org/pas-domain) houses the nuclear localization signal.<sup>[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7351129/)</sup>

NCOA2 also has a centrally located repression domain that bears no similarity to the other NCOAs or any known proteins, and it can act as a transcription regulator inhibitor as well as a coactivator.<sup>[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)</sup><sup> • </sup><sup>[9](https://pubchem.ncbi.nlm.nih.gov/gene/10499)</sup> The protein is subject to post-translational modification: glucocorticoid-dependent phosphorylation at S469, S487, S493, and S499 potentiates activation of a subset of glucocorticoid receptor targets.<sup>[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)</sup>

## Role in cancer

**Chromosomal fusions.** In several cancers, this gene undergoes translocations that yield fused oncogenes: fusion to [KAT6A](https://www.edgepedia.org/kat6a) (lysine acetyltransferase 6A) occurs in acute myeloid leukemia, fusion to ETV6 (ETS variant 6) in acute lymphoblastic leukemia, and fusion to [HEY1](https://www.edgepedia.org/hey1) in mesenchymal chondrosarcoma.<sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup> Through the rearrangement inv(8)(p11;q13), the KAT6A-NCOA2 oncogene arises, combining the N-terminal portion of KAT6A with the C-terminal portion of NCOA2; the resulting fusion protein attaches to CREBBP and interferes with its role in activating transcription.<sup>[4](https://www.genecards.org/card/NCOA2)</sup>

**Rhabdomyosarcoma.** In spindle-cell infantile and pediatric rhabdomyosarcoma, additional NCOA2 fusions have been identified, including VGLL2::NCOA2, TEAD1::NCOA2, and SRF::NCOA2.<sup>[3](https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1570070/pdf)</sup> A structure-function analysis of VGLL2::NCOA2 in a mouse myoblast model defined the domain requirements for transformation, with the goal of identifying molecular targets that can suppress fusion activity.<sup>[10](https://www.aacr.org/wp-content/uploads/2025/05/AACR2025_Proceedings_050725.pdf)</sup>

**Prostate cancer.** NCOA2 is amplified or overexpressed in 8% of primary prostate tumors, with a higher frequency of 37% in metastatic cancer, and patients bearing higher NCOA2 levels are more likely to relapse after androgen deprivation therapy. Genetically engineered mouse models and patient specimen analysis indicate that androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer.<sup>[6](https://www.jci.org/articles/view/76412)</sup> NCBI Gene also lists the gene as implicated in colorectal carcinoma and lung non-small cell carcinoma, and as a biomarker for several cancers including colorectal adenocarcinoma, malignant pleural mesothelioma, prostate cancer, and stomach cancer.<sup>[9](https://pubchem.ncbi.nlm.nih.gov/gene/10499)</sup>

## Physiology and metabolism

Mouse studies show overlapping but distinct roles for the p160 coactivators. NCOA2-ablated mice of both genders are hypofertile: males exhibit disrupted spermatogenesis and an age-dependent testicular degeneration preceded by defective lipid metabolism in Sertoli cells, while females have hypoplastic placentas. Disrupted adrenal architecture in knockout mice also deregulates the hypothalamic-pituitary-adrenal axis.<sup>[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)</sup>

Metabolic profiling of NCOA2 knockout mice showed a phenotype reciprocal to that of NCOA1 knockout: enhanced energy expenditure, protection against obesity, and increased insulin sensitivity, effects attributed to the preferential formation of more stable NCOA1:PGC1α complexes that drive transactivation of energy-consumption genes such as Ucp1.<sup>[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)</sup> NCOA2 also facilitates fasting glucose release from the liver by activating glucose-6-phosphatase expression, acting as the dedicated coactivator for the retinoid-related orphan receptor RORα in that context.<sup>[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)</sup> In immune biology, Ncoa2 promotes CD8+ T cell-mediated antitumor immunity by stimulating T-cell activation through upregulation of PGC-1α, which is critical for mitochondrial function.<sup>[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC10592187/)</sup>

## Nomenclature and identifiers

The gene's aliases reflect its discovery history: GRIP1 (glucocorticoid receptor-interacting protein 1) and TIF2 (transcriptional intermediary factor 2) were assigned when the protein was cloned in 1996 as a 160 kDa nuclear protein interacting with nuclear receptors in an agonist-dependent manner, and SRC-2 places it second in the steroid receptor coactivator family.<sup>[7](https://affinage.wi.mit.edu/gene/NCOA2)</sup><sup> • </sup><sup>[12](https://genesdev.cshlp.org/content/early/2025/12/18/gad.353393.125.full.pdf)</sup> NCBI notes that GRIP1 is a widely used alternative name for NCOA2 that can be confused with the official symbol of glutamate receptor-interacting protein 1 (Gene ID 23426).<sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup> The MANE Select transcript is NM_006540.4 / ENST00000452400.7, and alternative splicing produces multiple transcript variants.<sup>[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669)</sup><sup> • </sup><sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup> Expression is ubiquitous across human tissues, with the highest reported RNA levels in testis (RPKM 5.6) and esophagus (RPKM 4.0).<sup>[1](https://www.ncbi.nlm.nih.gov/gene/10499)</sup> Orthologs exist in mouse (MGI:1276533), rat, and zebrafish, and the human gene is implicated through these models in acute myeloid leukemia, colorectal carcinoma, lung non-small cell carcinoma, and prostate adenocarcinoma.<sup>[13](https://www.informatics.jax.org/marker/MGI%3A1276533)</sup><sup> • </sup><sup>[14](https://zfin.org/ZDB-GENE-010406-3)</sup>

## References

1. [NCOA2 nuclear receptor coactivator 2 [Homo sapiens] – NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/10499)
2. [NCOA2 curation results – ClinGen](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669)
3. [Sankhe CS, Hall L, Kendall GC (2025). Fusion oncogenes in rhabdomyosarcoma. Front. Oncol. 15:1570070](https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1570070/pdf)
4. [NCOA2 Gene – GeneCards](https://www.genecards.org/card/NCOA2)
5. [Nuclear Receptor Coactivators (NCOAs) and Corepressors (NCORs) in the Brain – Endocrinology](https://pmc.ncbi.nlm.nih.gov/articles/PMC7351129/)
6. [Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer – JCI](https://www.jci.org/articles/view/76412)
7. [NCOA2 – Affinage (MIT)](https://affinage.wi.mit.edu/gene/NCOA2)
8. [Minireview: Nuclear Receptor Coregulators of the p160 Family – PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)
9. [NCOA2 (human) | Gene Target – PubChem](https://pubchem.ncbi.nlm.nih.gov/gene/10499)
10. [VGLL2::NCOA2 structure-function analysis – AACR 2025 Proceedings](https://www.aacr.org/wp-content/uploads/2025/05/AACR2025_Proceedings_050725.pdf)
11. [Ncoa2 promotes CD8+ T cell-mediated anti-tumor immunity – PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10592187/)
12. [Nuclear receptor coregulator interactions: beyond the switch – Genes & Development](https://genesdev.cshlp.org/content/early/2025/12/18/gad.353393.125.full.pdf)
13. [Ncoa2 MGI Mouse Gene Detail – MGI:1276533](https://www.informatics.jax.org/marker/MGI%3A1276533)
14. [ZFIN Gene: ncoa2](https://zfin.org/ZDB-GENE-010406-3)

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*Topic: Encyclopedia › Life and health › Biological foundations › Genetics and genomic reference › Human gene and locus records › Transcription factors and regulators › Nuclear receptors*

*Initially written Oct 21, 2026*

*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*

License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license