{ "id": "epepjhd3e8", "slug": "ncoa2", "title": "NCOA2", "updated": "2026-10-21", "topic_path": [ { "id": "life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/topics/life" }, { "id": "life.biology", "label": "Biological foundations", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology" }, { "id": "life.biology.genetics", "label": "Genetics and genomic reference", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics" }, { "id": "life.biology.genetics.gene_record_human", "label": "Human gene and locus records", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics.gene_record_human" }, { "id": "life.biology.genetics.gene_record_human.transcription-factors-and-regulators", "label": "Transcription factors and regulators", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics.gene_record_human.transcription-factors-and-regulators" }, { "id": "life.biology.genetics.gene_record_human.transcription-factors-and-regulators.nuclear-receptors", "label": "Nuclear receptors", "api_url": "https://www.edgepedia.org/api/v1/topics/life.biology.genetics.gene_record_human.transcription-factors-and-regulators.nuclear-receptors" } ], "geo": [ { "id": "geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators.nuclear-receptors", "label": "Non-geographic · Not dated: Nuclear receptors", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators.nuclear-receptors", "path": [ { "id": "geo.nongeo", "label": "Non-geographic", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo" }, { "id": "geo.nongeo.nodate", "label": "Non-geographic · Not dated", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate" }, { "id": "geo.nongeo.nodate.life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life" }, { "id": "geo.nongeo.nodate.life.biology", "label": "Biological foundations", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology" }, { "id": "geo.nongeo.nodate.life.biology.genetics", "label": "Genetics and genomic reference", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics" }, { "id": "geo.nongeo.nodate.life.biology.genetics.gene_record_human", "label": "Human gene and locus records", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics.gene_record_human" }, { "id": "geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators", "label": "Transcription factors and regulators", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators" }, { "id": "geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators.nuclear-receptors", "label": "Nuclear receptors", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.nodate.life.biology.genetics.gene_record_human.transcription-factors-and-regulators.nuclear-receptors" } ] } ], "excerpt": "NCOA2 (SRC-2, TIF2, GRIP1), nuclear receptor coactivator 2, is a p160-family transcriptional coactivator gene on 8q13.3, a fusion partner in leukemia, chondrosarcoma, and rhabdomyosarcoma and amplified in prostate cancer.", "snippet": "NCOA2 (SRC-2, TIF2, GRIP1), nuclear receptor coactivator 2, is a p160-family transcriptional coactivator gene on 8q13.3, a fusion partner in leukemia, chondrosarcoma, and rhabdomyosarcoma and amplified in prostate cancer.", "node": "life.biology.genetics.gene_record_human.transcription-factors-and-regulators.nuclear-receptors", "markdown": "# NCOA2\n\n**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.[1](https://www.ncbi.nlm.nih.gov/gene/10499) • [2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669) 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.[1](https://www.ncbi.nlm.nih.gov/gene/10499) The gene is also a recurring fusion partner in several cancers, including acute myeloid leukemia, acute lymphoblastic leukemia, mesenchymal chondrosarcoma, and spindle-cell rhabdomyosarcoma.[1](https://www.ncbi.nlm.nih.gov/gene/10499) • [3](https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1570070/pdf)\n\n| Key fact | Detail |\n|---|---|\n| Official name | Nuclear receptor coactivator 2; HGNC:7669, Entrez Gene ID 10499, OMIM 601993, UniProt Q15596[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669) • [4](https://www.genecards.org/card/NCOA2) |\n| Location | Chromosome 8q13.3; GRCh38 chr8:70,109,782–70,456,446 (minus strand); 35 exons[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669) • [1](https://www.ncbi.nlm.nih.gov/gene/10499) |\n| 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[4](https://www.genecards.org/card/NCOA2) • [5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7351129/) |\n| Main aliases | SRC-2, TIF2, GRIP1, NCoA-2, KAT13C, bHLHe75[1](https://www.ncbi.nlm.nih.gov/gene/10499) |\n| Cancer fusions | KAT6A-NCOA2 in acute myeloid leukemia, ETV6-NCOA2 in acute lymphoblastic leukemia, HEY1-NCOA2 in mesenchymal chondrosarcoma[1](https://www.ncbi.nlm.nih.gov/gene/10499) |\n| Prostate cancer | Amplified or overexpressed in 8% of primary tumors and 37% of metastatic prostate cancers[6](https://www.jci.org/articles/view/76412) |\n| Loss-of-function constraint | gnomAD pLI of 1 and LOEUF of 0.21, indicating strong intolerance of loss-of-function variation[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669) |\n\n## Function and mechanism\n\nNCOA2 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.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7351129/) 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.[6](https://www.jci.org/articles/view/76412)\n\nReceptor 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.[7](https://affinage.wi.mit.edu/gene/NCOA2) • [8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/) The N-terminal basic helix-loop-helix-[PAS domain](https://www.edgepedia.org/pas-domain) houses the nuclear localization signal.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7351129/)\n\nNCOA2 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.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/) • [9](https://pubchem.ncbi.nlm.nih.gov/gene/10499) 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.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)\n\n## Role in cancer\n\n**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.[1](https://www.ncbi.nlm.nih.gov/gene/10499) 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.[4](https://www.genecards.org/card/NCOA2)\n\n**Rhabdomyosarcoma.** In spindle-cell infantile and pediatric rhabdomyosarcoma, additional NCOA2 fusions have been identified, including VGLL2::NCOA2, TEAD1::NCOA2, and SRF::NCOA2.[3](https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1570070/pdf) 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.[10](https://www.aacr.org/wp-content/uploads/2025/05/AACR2025_Proceedings_050725.pdf)\n\n**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.[6](https://www.jci.org/articles/view/76412) 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.[9](https://pubchem.ncbi.nlm.nih.gov/gene/10499)\n\n## Physiology and metabolism\n\nMouse 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.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)\n\nMetabolic 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.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/) 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.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/) 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.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC10592187/)\n\n## Nomenclature and identifiers\n\nThe 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.[7](https://affinage.wi.mit.edu/gene/NCOA2) • [12](https://genesdev.cshlp.org/content/early/2025/12/18/gad.353393.125.full.pdf) 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).[1](https://www.ncbi.nlm.nih.gov/gene/10499) The MANE Select transcript is NM_006540.4 / ENST00000452400.7, and alternative splicing produces multiple transcript variants.[2](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669) • [1](https://www.ncbi.nlm.nih.gov/gene/10499) Expression is ubiquitous across human tissues, with the highest reported RNA levels in testis (RPKM 5.6) and esophagus (RPKM 4.0).[1](https://www.ncbi.nlm.nih.gov/gene/10499) 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.[13](https://www.informatics.jax.org/marker/MGI%3A1276533) • [14](https://zfin.org/ZDB-GENE-010406-3)\n\n## References\n\n1. [NCOA2 nuclear receptor coactivator 2 [Homo sapiens] – NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/10499)\n2. [NCOA2 curation results – ClinGen](https://search.clinicalgenome.org/kb/genes/HGNC%3A7669)\n3. [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)\n4. [NCOA2 Gene – GeneCards](https://www.genecards.org/card/NCOA2)\n5. [Nuclear Receptor Coactivators (NCOAs) and Corepressors (NCORs) in the Brain – Endocrinology](https://pmc.ncbi.nlm.nih.gov/articles/PMC7351129/)\n6. [Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer – JCI](https://www.jci.org/articles/view/76412)\n7. [NCOA2 – Affinage (MIT)](https://affinage.wi.mit.edu/gene/NCOA2)\n8. [Minireview: Nuclear Receptor Coregulators of the p160 Family – PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4399279/)\n9. [NCOA2 (human) | Gene Target – PubChem](https://pubchem.ncbi.nlm.nih.gov/gene/10499)\n10. [VGLL2::NCOA2 structure-function analysis – AACR 2025 Proceedings](https://www.aacr.org/wp-content/uploads/2025/05/AACR2025_Proceedings_050725.pdf)\n11. [Ncoa2 promotes CD8+ T cell-mediated anti-tumor immunity – PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10592187/)\n12. [Nuclear receptor coregulator interactions: beyond the switch – Genes & Development](https://genesdev.cshlp.org/content/early/2025/12/18/gad.353393.125.full.pdf)\n13. [Ncoa2 MGI Mouse Gene Detail – MGI:1276533](https://www.informatics.jax.org/marker/MGI%3A1276533)\n14. [ZFIN Gene: ncoa2](https://zfin.org/ZDB-GENE-010406-3)\n\n---\n*Topic: Encyclopedia › Life and health › Biological foundations › Genetics and genomic reference › Human gene and locus records › Transcription factors and regulators › Nuclear receptors*\n\n*Initially written Oct 21, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/ncoa2", "markdown_url": "https://www.edgepedia.org/ncoa2.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"NCOA2\", Edgepedia (EdgeChat), https://www.edgepedia.org/ncoa2. Edgepedia Community License 1.0.", "credit_md": "\"[NCOA2](https://www.edgepedia.org/ncoa2)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/ncoa2](https://www.edgepedia.org/ncoa2). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"NCOA2\", Edgepedia (EdgeChat), https://www.edgepedia.org/ncoa2. Edgepedia Community License 1.0.", "speakable": "NCOA2, nuclear receptor coactivator 2, is a p160-family transcriptional coactivator gene on 8q13.3, a fusion partner in leukemia, chondrosarcoma, and rhabdomyosarcoma and amplified in prostate cancer." }