NCOA2 Gene

HGNC Family	Chromatin-modifying enzymes, Basic helix-loop-helix proteins (BHLH)
Name	nuclear receptor coactivator 2
Description	The protein encoded by this gene functions as a transcriptional coactivator for nuclear hormone receptors, including steroid, thyroid, retinoid, and vitamin D receptors. The encoded protein acts as an intermediary factor for the ligand-dependent activity of these nuclear receptors, which regulate their target genes upon binding of cognate response elements. This gene has been found to be involved in translocations that result in fusions with other genes in various cancers, including the lysine acetyltransferase 6A (KAT6A) gene in acute myeloid leukemia, the ETS variant 6 (ETV6) gene in acute lymphoblastic leukemia, and the hes related family bHLH transcription factor with YRPW motif 1 (HEY1) gene in mesenchymal chondrosarcoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNCOA2, also known as steroid receptor coactivator‐2 (SRC‐2), TIF2, or GRIP1, is a nuclear receptor coactivator that plays a central role in modulating transcriptional programs in diverse biological contexts. Its normal function is to physically interact with nuclear receptors and other transcription factors in order to enhance transcription of target genes by recruiting additional coactivators (such as CBP) and chromatin modifiers. This activity is critical in regulating differentiation, proliferation, metabolic pathways, and hormone signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPathologically, recurrent fusion events involving NCOA2 with transcription factors have been identified in several malignancies. For example, in mesenchymal chondrosarcomas the discovery of a HEY1-NCOA2 fusion defines a diagnostic marker for these tumors, while in pediatric spindle cell rhabdomyosarcoma, SRF-NCOA2 or TEAD1-NCOA2 fusions have been detected, suggesting that the aberrant merging of NCOA2’s activation domains with partner sequences drives tumor-specific transcriptional programs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hematologic malignancies, the MOZ-TIF2 fusion—where TIF2 represents NCOA2—has been shown to be essential for leukemic transformation. The fusion protein retains crucial domains from NCOA2 that mediate interaction with CBP, thereby subverting normal transcriptional control to promote acute myeloid leukemia. Similar mechanistic paradigms are seen in solid tumors where deregulated coactivator activity underpins oncogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hormone‐responsive cancers such as prostate and breast carcinomas, NCOA2 is a key modulator of androgen and estrogen receptor activity. In prostate cancer, for instance, epidermal growth factor (EGF)–mediated MAPK signaling increases TIF2/GRIP1 levels, leading to enhanced androgen receptor transactivation and contributing to treatment resistance. Similarly, IL-6 exposure has been shown to upregulate TIF2, correlating with bicalutamide resistance in prostate cancer cells. In breast cancer cells, loss-of-function studies reveal that depletion of SRC-2/NCOA2 diminishes estrogen-dependent proliferation and alters survival pathways, highlighting its nonredundant role among p160 family members."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in transcriptional regulation related to hormone signaling and oncogenic fusion proteins, NCOA2 is a critical mediator of metabolic reprogramming and energy homeostasis. Upregulation of SRC-2 stimulates glutamine-dependent de novo lipogenesis, thereby promoting survival and metastasis in prostate cancer, while in the liver the AMPK–SRC-2 axis facilitates absorption and systemic utilization of dietary fats. Moreover, SRC-2 is essential during endometrial stromal cell decidualization by enhancing glycolytic flux through induction of key enzymes such as PFKFB3, highlighting its role in reproductive homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, pharmacological studies demonstrate that hyperactivation of SRC coactivators, including NCOA2, using small molecule stimulators like MCB-613, can overdrive transcriptional programs to induce endoplasmic reticulum stress and cancer cell death. In parallel, cooperative recruitment of NCOA2 by ligand-bound nuclear receptor heterodimers (for example, PPARγ–RXRα) underscores how DNA and ligand signals synergize through conformational and dynamic changes in the receptor–coactivator complex to regulate gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies in uterine tumors, specifically uterine tumors resembling ovarian sex‐cord tumors (UTROSCT), have revealed recurrent fusion events (e.g., ESR1–NCOA2 or GREB1–NCOA2) that distinguish these neoplasms from other uterine cancers and further emphasize the diagnostic and pathogenic significance of NCOA2 rearrangements. Alongside, investigations contrasting steroid receptor RNA activator (SRA) with SRC proteins illustrate that while these coactivators can cooperate to enhance estrogen receptor signaling, they also fulfill unique, non-overlapping roles in regulating receptor-dependent transcription."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these findings underscore the multifaceted roles of NCOA2 in normal cellular physiology and tumorigenesis. Whether acting as a component of oncogenic fusion proteins, as a modulator of nuclear receptor activity influencing cell proliferation and therapeutic outcomes, or as an essential coordinator of metabolic and energy homeostasis, NCOA2 emerges as a pivotal transcriptional regulator with considerable potential as both a diagnostic marker and therapeutic target across a spectrum of cancers and other pathologies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}, {"type": "fg_fs", "start_ref": "5", "end_ref": "7"}, {"type": "fg_fs", "start_ref": "12", "end_ref": "14"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "17"}, {"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "16"}, {"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lu Wang, Toru Motoi, Raya Khanin, et al. 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Synonyms	KAT13C, GRIP1, NCOA-2, BHLHE75, TIF2
Proteins	NCOA2_HUMAN
NCBI Gene ID	10499
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

NCOA2 has 9,472 functional associations with biological entities spanning 8 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 136 datasets.

Click the + buttons to view associations for NCOA2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

NCOA2 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by NCOA2 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of NCOA2 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of NCOA2 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of NCOA2 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of NCOA2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of NCOA2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Biocarta Pathways	pathways involving NCOA2 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of NCOA2 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of NCOA2 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of NCOA2 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of NCOA2 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of NCOA2 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of NCOA2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with NCOA2 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with NCOA2 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with NCOA2 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of NCOA2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of NCOA2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of NCOA2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing NCOA2 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of NCOA2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing NCOA2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing NCOA2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with NCOA2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with NCOA2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing NCOA2 protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of NCOA2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with NCOA2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with NCOA2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with NCOA2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with NCOA2 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of NCOA2 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by NCOA2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with NCOA2 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with NCOA2 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with NCOA2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with NCOA2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with NCOA2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with NCOA2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for NCOA2 protein from the curated DrugBank Drug Targets dataset.