RPS6KA2 Gene

Name	ribosomal protein S6 kinase, 90kDa, polypeptide 2
Description	This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains two non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Alternative splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2016]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRPS6KA2, which encodes p90RSK3, has emerged as a key modulator in signal transduction that governs cell survival and proliferation. In breast cancer, overexpression of RPS6KA2 supports cell proliferation under PI3K/mTOR blockade by attenuating the apoptotic response and enhancing protein translation, thereby contributing to resistance against PI3K inhibitors. Furthermore, studies have shown that RPS6KA2 functions as a downstream substrate of MAP kinases such as ERK5, which can directly phosphorylate and activate it, integrating mitogenic signals into adaptive cellular responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast to its protumorigenic role in certain contexts, RPS6KA2 also exhibits tumor-suppressive properties. In ovarian cancer, RPS6KA2 is normally expressed in the epithelium, but its loss—often via monoallelic expression or gene deletions—is associated with increased tumorigenicity, as re-expression leads to G1 cell cycle arrest, enhanced apoptosis, and reduced colony formation. In addition, genetic variation within the RPS6KA2 locus has been linked to altered risks for colon and rectal cancers, underscoring its broader significance in tumor biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRPS6KA2 is also implicated in mediating resistance to targeted anticancer therapies. In pancreatic cancer models, RPS6KA2 acts downstream of EGFR/RAS/MEK/ERK signaling to block EGFR inhibitor–induced apoptosis, while in small cell lung cancer, BET bromodomain inhibitor treatment leads to upregulation and activation of RPS6KA2. In these settings, its kinase activity—induced via phosphorylation by ERK isoforms—triggers pro-survival cascades, such as the TSC2-mTOR-p70S6K1-BAD pathway, thereby diminishing the efficacy of agents like erlotinib or BET inhibitors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer, emerging evidence suggests that genetic variations and specific haplotypes involving RPS6KA2 may influence the responsiveness to pharmacological treatments, such as antidepressants, potentially by altering MAPK pathway signaling and downstream effector functions. These observations highlight the multifaceted contributions of RPS6KA2 in diverse biological systems and its promise as both a prognostic marker and a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Violeta Serra, Pieter J A Eichhorn, Celina García-García, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI66343"}], "href": "https://doi.org/10.1172/JCI66343"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23635776"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23635776"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Aarati Ranganathan, Gray W Pearson, Carol A Chrestensen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The MAP kinase ERK5 binds to and phosphorylates p90 RSK."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.abb.2006.02.023"}], "href": "https://doi.org/10.1016/j.abb.2006.02.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16626623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16626623"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "P A Bignone, K Y Lee, Y Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1209827"}], "href": "https://doi.org/10.1038/sj.onc.1209827"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16878154"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16878154"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Martha L Slattery, Abbie Lundgreen, Jennifer S Herrick, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic variation in RPS6KA1, RPS6KA2, RPS6KB1, RPS6KB2, and PDK1 and risk of colon or rectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mutat Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mrfmmm.2010.10.005"}], "href": "https://doi.org/10.1016/j.mrfmmm.2010.10.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21035469"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21035469"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Nada Milosevic, Benjamin Kühnemuth, Leonie Mühlberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neoplasia (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1593/neo.131660"}], "href": "https://doi.org/10.1593/neo.131660"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24403857"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24403857"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Fang Tai, Kunxiang Gong, Kai Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-019-14083-4"}], "href": "https://doi.org/10.1038/s41467-019-14083-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31937753"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31937753"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Anju Kumari, Lisa Gesumaria, Yan-Jin Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JCI Insight (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/jci.insight.156657"}], "href": "https://doi.org/10.1172/jci.insight.156657"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36883564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36883564"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Cong-jie Wang, Zhi-jun Zhang, Zhi Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kinase gene haplotypes and gene-gene interactions in the Ras-Raf-MAPK signaling pathway: association with antidepressant remission."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Clin Psychopharmacol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/YIC.0b013e328362c89f"}], "href": "https://doi.org/10.1097/YIC.0b013e328362c89f"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23727904"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23727904"}]}]}]}
Synonyms	p90RSK2, S6K-ALPHA, PP90RSK3, P90-RSK3, MAPKAPK1C, S6K-ALPHA2, RSK3
Proteins	KS6A2_HUMAN
NCBI Gene ID	6196
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

RPS6KA2 has 9,403 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 127 datasets.

Click the + buttons to view associations for RPS6KA2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

RPS6KA2 Gene

Functional Associations

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

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of RPS6KA2 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 RPS6KA2 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of RPS6KA2 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 RPS6KA2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of RPS6KA2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of RPS6KA2 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 RPS6KA2 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 RPS6KA2 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of RPS6KA2 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 RPS6KA2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with RPS6KA2 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with RPS6KA2 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with RPS6KA2 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 RPS6KA2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of RPS6KA2 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 RPS6KA2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of RPS6KA2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing RPS6KA2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing RPS6KA2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing RPS6KA2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with RPS6KA2 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 RPS6KA2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of RPS6KA2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with RPS6KA2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with RPS6KA2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with RPS6KA2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with RPS6KA2 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 RPS6KA2 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 RPS6KA2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving RPS6KA2 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with RPS6KA2 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 RPS6KA2 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 RPS6KA2 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 RPS6KA2 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 RPS6KA2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with RPS6KA2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at RPS6KA2 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of RPS6KA2 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of RPS6KA2 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing RPS6KA2 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.