P18654 (KS6A3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ribosomal protein S6 kinase alpha-3
Short name=S6K-alpha-3
EC=2.7.11.1

Alternative name(s):
90 kDa ribosomal protein S6 kinase 3
Short name=p90-RSK 3
Short name=p90RSK3
MAP kinase-activated protein kinase 1b
Short name=MAPK-activated protein kinase 1b
Short name=MAPKAP kinase 1b
Short name=MAPKAPK-1b
Ribosomal S6 kinase 2
Short name=RSK-2
pp90RSK2

Gene names

Name:	Rps6ka3
Synonyms:	Mapkapk1b, Rps6ka-rs1, Rsk2

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	740 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. 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. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Phosphorylates DAPK1 By similarity. Ref.5 Ref.7 Ref.8 Ref.9
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity.
Enzyme regulation	Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-577 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-386, allowing binding of PDPK1, which in turn phosphorylates Ser-227 in the N-terminal kinase domain (NTDK) leading to the full activation of the protein and subsequent phosphorylation of the substrates by the NTKD By similarity. Ref.4 Ref.5
Subunit structure	Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation By similarity. Interacts with NFATC4, ETV1/ER81 and FGFR1 By similarity.
Subcellular location	Nucleus By similarity. Cytoplasm By similarity.
Tissue specificity	Intestine, thymus, lung, heart and brain.
Post-translational modification	Activated by phosphorylation at Ser-227 by PDPK1. Autophosphorylated on Ser-386, as part of the activation process. May be phosphorylated at Thr-365 and Ser-369 by MAPK1/ERK2 and MAPK3/ERK1. Can also be activated via phosphorylation at Ser-386 by MAPKAPK2. Ref.4 Ref.8 Ref.9 N-terminal myristoylation results in an activated kinase in the absence of added growth factors By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 2 protein kinase domains.

Ontologies

Keywords
Biological process	Cell cycle Stress response
Cellular component	Cytoplasm Nucleus
Domain	Repeat
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell cycle Inferred from electronic annotation. Source: UniProtKB-KW intracellular protein kinase cascade Inferred from electronic annotation. Source: InterPro positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara response to lipopolysaccharide Inferred from mutant phenotype Ref.9. Source: UniProtKB response to stress Inferred from electronic annotation. Source: UniProtKB-KW toll-like receptor signaling pathway Inferred from mutant phenotype Ref.9. Source: UniProtKB
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cysteine-type endopeptidase inhibitor activity involved in apoptotic process Inferred from electronic annotation. Source: Compara magnesium ion binding Inferred from electronic annotation. Source: InterPro protein serine/threonine kinase activity Inferred from direct assay Ref.1. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 740

740

Ribosomal protein S6 kinase alpha-3

PRO_0000086204

Regions

Domain

68 – 327

260

Protein kinase 1

Domain

328 – 397

70

AGC-kinase C-terminal

Domain

422 – 679

258

Protein kinase 2

Nucleotide binding

74 – 82

9

ATP By similarity

Nucleotide binding

428 – 436

9

ATP By similarity

Sites

Active site

193

1

Proton acceptor By similarity

Active site

539

1

Proton acceptor By similarity

Binding site

100

1

ATP By similarity

Binding site

451

1

ATP By similarity

Amino acid modifications

Modified residue

227

1

Phosphoserine; by PDPK1 Ref.4

Modified residue

365

1

Phosphothreonine Ref.6

Modified residue

369

1

Phosphoserine Ref.6

Modified residue

375

1

Phosphoserine By similarity

Modified residue

386

1

Phosphoserine; by autocatalysis and MAPKAPK2 Ref.4 Ref.9

Modified residue

415

1

Phosphoserine By similarity

Modified residue

529

1

Phosphotyrosine; by FGFR3 Ref.8

Modified residue

556

1

Phosphoserine By similarity

Modified residue

715

1

Phosphoserine By similarity

Experimental info

Mutagenesis

227

1

S → E: Loss of phosphorylation and activation by PDPK1. Ref.4

Mutagenesis

386

1

S → A: Loss of phosphorylation by PDPK1; loss of activation by PDPK1 and EGF. Ref.4 Ref.5

Mutagenesis

386

1

S → E: Loss of interaction with PDPK1 and phosphorylation at S-227. Ref.4 Ref.5

Mutagenesis

529

1

Y → F: Attenuates activation by MAPK1/ERK1 and MAPK3/ERK2. Ref.8

Secondary structure

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740

Helix Strand Turn

Details...

Beta strand

50 – 56

7

Helix

65 – 67

3

Beta strand

68 – 75

8

Helix

77 – 79

3

Beta strand

81 – 87

7

Turn

91 – 94

4

Beta strand

96 – 111

16

Helix

121 – 124

4

Beta strand

133 – 139

7

Beta strand

142 – 147

6

Helix

156 – 162

7

Helix

167 – 186

20

Helix

196 – 198

3

Beta strand

199 – 201

3

Beta strand

207 – 216

10

Helix

232 – 234

3

Helix

237 – 241

5

Helix

248 – 263

16

Helix

273 – 282

10

Helix

293 – 302

10

Helix

307 – 309

3

Turn

315 – 317

3

Helix

318 – 322

5

Helix

325 – 327

3

Helix

332 – 336

5

Helix

418 – 421

4

Beta strand

422 – 430

9

Beta strand

432 – 441

10

Turn

442 – 444

3

Beta strand

447 – 454

8

Turn

455 – 457

3

Helix

461 – 470

10

Beta strand

479 – 484

6

Beta strand

486 – 493

8

Helix

501 – 506

6

Helix

513 – 532

20

Helix

542 – 544

3

Beta strand

545 – 551

7

Helix

554 – 556

3

Beta strand

557 – 559

3

Helix

587 – 613

27

Helix

626 – 635

10

Turn

643 – 647

5

Helix

650 – 659

10

Turn

664 – 666

3

Helix

670 – 673

4

Helix

677 – 680

4

Helix

682 – 684

3

Helix

696 – 710

15

Turn

711 – 713

3

Sequences

	Sequence		Length	Mass (Da)
	P18654 [UniParc]. Last modified March 25, 2003. Version 2. Checksum: 0CD54E5918567007	FASTA	740	83,694
	10 20 30 40 50 60 MPLAQLADPW QKMAVESPSD SAENGQQIMD EPMGEEEINP QTEEGSIKEI AITHHVKEGH 70 80 90 100 110 120 EKADPSQFEL LKVLGQGSFG KVFLVKKISG SDARQLYAMK VLKKATLKVR DRVRTKMERD 130 140 150 160 170 180 ILVEVNHPFI VKLHYAFQTE GKLYLILDFL RGGDLFTRLS KEVMFTEEDV KFYLAELALA 190 200 210 220 230 240 LDHLHSLGII YRDLKPENIL LDEEGHIKLT DFGLSKESID HEKKAYSFCG TVEYMAPEVV 250 260 270 280 290 300 NRRGHTQSAD WWSFGVLMFE MLTGTLPFQG KDRKETMTMI LKAKLGMPQF LSPEAQSLLR 310 320 330 340 350 360 MLFKRNPANR LGAGPDGVEE IKRHSFFSTI DWNKLYRREI HPPFKPATGR PEDTFYFDPE 370 380 390 400 410 420 FTAKTPKDSP GIPPSANAHQ LFRGFSFVAI TSDDESQAMQ TVGVHSIVQQ LHRNSIQFTD 430 440 450 460 470 480 GYEVKEDIGV GSYSVCKRCI HKATNMEFAV KIIDKSKRDP TEEIEILLRY GQHPNIITLK 490 500 510 520 530 540 DVYDDGKYVY VVTELMKGGE LLDKILRQKF FSEREASAVL FTITKTVEYL HAQGVVHRDL 550 560 570 580 590 600 KPSNILYVDE SGNPESIRIC DFGFAKQLRA ENGLLMTPCY TANFVAPEVL KRQGYDAACD 610 620 630 640 650 660 IWSLGVLLYT MLTGYTPFAN GPDDTPEEIL ARIGSGKFSL SGGYWNSVSD TAKDLVSKML 670 680 690 700 710 720 HVDPHQRLTA ALVLRHPWIV HWDQLPQYQL NRQDAPHLVK GAMAATYSAL NRNQSPVLEP 730 740 VGRSTLAQRR GIKKITSTAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of the p90 ribosomal S6 kinase 2 carboxyl-terminal domain as a protein kinase." Chrestensen C.A., Sturgill T.W. J. Biol. Chem. 277:27733-27741(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[3]	"Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase." Alcorta D.A., Crews C.M., Sweet L.J., Bankston L., Jones S.W., Erikson R.L. Mol. Cell. Biol. 9:3850-3859(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 108-740.
[4]	"90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1." Jensen C.J., Buch M.-B., Krag T.O., Hemmings B.A., Gammeltoft S., Froedin M. J. Biol. Chem. 274:27168-27176(1999) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION, PHOSPHORYLATION AT SER-227 AND SER-386, MUTAGENESIS OF SER-227 AND SER-386.
[5]	"A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1." Froedin M., Jensen C.J., Merienne K., Gammeltoft S. EMBO J. 19:2924-2934(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME REGULATION, MUTAGENESIS OF SER-386.
[6]	"Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry." Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J., Faessler R., Mann M. J. Proteome Res. 7:5314-5326(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-365 AND SER-369, MASS SPECTROMETRY. Tissue: Melanoma.
[7]	"Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization." Fujita N., Sato S., Tsuruo T. J. Biol. Chem. 278:49254-49260(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF CDKN1B.
[8]	"FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway." Kang S., Dong S., Gu T.L., Guo A., Cohen M.S., Lonial S., Khoury H.J., Fabbro D., Gilliland D.G., Bergsagel P.L., Taunton J., Polakiewicz R.D., Chen J. Cancer Cell 12:201-214(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN HEMATOPOIETIC TRANSFORMATION, PHOSPHORYLATION AT TYR-529, MUTAGENESIS OF TYR-529.
[9]	"The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways." Zaru R., Ronkina N., Gaestel M., Arthur J.S., Watts C. Nat. Immunol. 8:1227-1235(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN TOLL-LIKE RECEPTOR SIGNALING, PHOSPHORYLATION AT SER-386.
[10]	"Structural basis for activation of the autoinhibitory C-terminal kinase domain of p90 RSK2." Malakhova M., Tereshko V., Lee S.Y., Yao K., Cho Y.Y., Bode A., Dong Z. Nat. Struct. Mol. Biol. 15:112-113(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 399-740.
[11]	"Structural diversity of the active N-terminal kinase domain of p90 ribosomal S6 kinase 2." Malakhova M., Kurinov I., Liu K., Zheng D., D'Angelo I., Shim J.H., Steinman V., Bode A.M., Dong Z. PLoS ONE 4:E8044-E8044(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 44-367.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AY083469 mRNA. Translation: AAM00022.1.
AL808146 Genomic DNA. Translation: CAM25836.1.

IPI

IPI00114333.

PIR

C32571.
S30504.

RefSeq

NP_683747.1. NM_148945.1.

UniGene

Mm.328476.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2QR7	X-ray	2.00	A	399-740	[»]
2QR8	X-ray	2.00	A	399-740	[»]
3G51	X-ray	1.80	A	44-367	[»]
3UBD	X-ray	1.53	A	45-346	[»]
4EL9	X-ray	1.55	A	45-346	[»]
4GUE	X-ray	1.80	A	45-346	[»]

ProteinModelPortal

P18654.

SMR

P18654. Positions 49-714.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-31554N.

IntAct

P18654. 2 interactions.

MINT

MINT-1486771.

PTM databases

PhosphoSite

P18654.

Proteomic databases

PaxDb

P18654.

PRIDE

P18654.

Protocols and materials databases

DNASU

110651.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000033671; ENSMUSP00000033671; ENSMUSG00000031309.

GeneID

110651.

KEGG

mmu:110651.

UCSC

uc009usk.1. mouse.

Organism-specific databases

CTD

6197.

MGI

MGI:104557. Rps6ka3.

Phylogenomic databases

eggNOG

COG0515.

GeneTree

ENSGT00680000099806.

HOVERGEN

HBG108317.

InParanoid

B1AXN4.

KO

K04373.

OrthoDB

EOG402WRK.

Gene expression databases

ArrayExpress

P18654.

Bgee

P18654.

CleanEx

MM_RPS6KA3.

Genevestigator

P18654.

GermOnline

ENSMUSG00000031309. Mus musculus.

Family and domain databases

InterPro

IPR000961. AGC-kinase_C.
IPR011009. Kinase-like_dom.
IPR017892. Pkinase_C.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR016239. Ribosomal_S6_kinase_II.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00069. Pkinase. 2 hits.
PF00433. Pkinase_C. 1 hit.
[Graphical view]

PIRSF

PIRSF000606. Ribsml_S6_kin_2. 1 hit.

SMART

SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 2 hits.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 2 hits.

PROSITE

PS51285. AGC_KINASE_CTER. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 2 hits.
PS50011. PROTEIN_KINASE_DOM. 2 hits.
PS00108. PROTEIN_KINASE_ST. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P18654.

ChiTaRS

RPS6KA3. mouse.

EvolutionaryTrace

P18654.

NextBio

364399.

SOURCE

Search...

Entry information

Entry name

KS6A3_MOUSE

Accession

Primary (citable) accession number: P18654
Secondary accession number(s): B1AXN4, Q03140, Q8K3J8

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1990
Last sequence update:	March 25, 2003
Last modified:	May 1, 2013
This is version 135 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program