Ribosomal protein S6 kinase alpha-3 (RPS6KA3)

The protein contains 740 amino acids for an estimated molecular weight of 83736 Da.

 

Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1 (PubMed:9770464, PubMed:16223362, PubMed:17360704, PubMed:16213824). In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes (PubMed:9770464, PubMed:10436156). In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP (PubMed:16223362). Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity (PubMed:8250835). Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex (PubMed:17360704). In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation (PubMed:18508509, PubMed:18813292). Is involved in the mTOR nutrient-sensing pathway by directly phospho (updated: June 17, 2020)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Interpro domains
Total structural coverage: 52%
Model score: 24

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VariantDescription
dbSNP:rs56218010
CLS
CLS
CLS
MRX19
CLS
CLS
CLS
CLS
CLS
CLS
MRX19
a breast cancer sample
CLS
a gastric adenocarcinoma sample
a glioblastoma multiforme sample; somatic mutation
dbSNP:rs35026425
CLS

The reference OMIM entry for this protein is 300075

Ribosomal protein s6 kinase, 90-kd, 3; rps6ka3
Ribosomal s6 kinase 2; rsk2
Mitogen-activated protein kinase-activated protein kinase 1b; mapkapk1b
Mapkap kinase 1b
Ispk1

DESCRIPTION

The RPS6KA3 gene encodes a member of the RSK (ribosomal S6 kinase) family of growth factor-regulated serine/threonine kinases, known also as p90(rsk). RSK proteins contain 2 functional kinase catalytic domains: the N-terminal kinase domain belongs to the AGC kinase family (see 188830), and the C-terminal kinase domain belongs to the CamK family (see 604998). The kinase domains are connected by a 100-amino acid linker region containing a PDK (PDPK1; 605213) docking site. RSK proteins are directly phosphorylated and activated by MAPK proteins (e.g., ERK1; 601795) in response to growth factors, polypeptide hormones, and neurotransmitters, and then subsequently phosphorylate many substrates. RSKs appear to have important roles in cell cycle progression, differentiation, and cell survival (review by Marques Pereira et al., 2010).

CLONING

Bjorbaek et al. (1995) showed that the cDNA encoding RPS6KA3, which they called ISPK1, encodes a predicted protein of 740 amino acids. Zeniou et al. (2002) determined the expression of the RSK1 (RPS6KA1; 601684), RSK2, and RSK3 (RPS6KA2; 601685) genes in various human tissues, during mouse embryogenesis, and in mouse brain. The 3 RSK mRNAs were expressed in all human tissues and brain regions tested, supporting functional redundancy. However, tissue-specific variations in levels suggested that the proteins may also serve specific roles. The mouse Rsk3 gene was prominently expressed in the developing neural and sensory tissues, whereas Rsk1 gene expression was the strongest in various other tissues with high proliferative activity, suggesting distinct roles during development. In adult mouse brain, the highest levels of Rsk2 expression were observed in regions with high synaptic activity, including the neocortex, the hippocampus, and Purkinje cells. The authors suggested that in these areas, which are essential to cognitive function and learning, the RSK1 and RSK3 genes may not be able to fully compensate for a lack of RSK2 function.

GENE STRUCTURE

Jacquot et al. (1998) found that the open reading frame of the RPS6KA3 coding region contains 22 exons.

MAPPING

In a study of the region of the X chromosome (Xp22.2) within which the Coffin-Lowry syndrome (CLS; 303600) maps, Trivier et al. (1996) identified an expressed sequence tag (EST) that showed 100% homology with a cDNA coding for RPS6KA3. Its localization was independently confirmed by Bjorbaek et al. (1995).

GENE FUNCTION

During the immediate-early response of mammalian cells to mitogens, histone H3 (see 602810) is rapidly and transiently phosphorylated by one or more kinases. Sassone-Corsi et al. (1999) demonstrated that RSK2 was required for epidermal growth factor (EGF; 131530)-stimulated phosphorylation of H3. Fibroblasts derived from a CLS patient failed to exhibit EGF-stimulated phosphorylation of H3, although H3 was phosphorylated during mitosis. Introduction of the wildtype RSK2 gene restored EGF-stimulated phosphorylation of H3 in the CLS cells. In addition, disruption of the RSK2 gene by homologous recombination in murine embryonic stem cells abolished EGF-stimulated phosphorylation of H3. H3 appears to be a direct or indirect target of RSK2, suggesting to Sassone-Corsi et al. (1999) that chromatin remodeling might contribute to mitogen-activated protein kinase-regulated gene expression. Thomas et al. (2005) presented evidence suggesting that RSK2 is involved in regulation of excit ... More on the omim web site

Subscribe to this protein entry history

June 29, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 300075 was added.

Jan. 25, 2016: Protein entry updated
Automatic update: model status changed