Q9Z2B9 (KS6A4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ribosomal protein S6 kinase alpha-4
Short name=S6K-alpha-4
EC=2.7.11.1

Alternative name(s):
90 kDa ribosomal protein S6 kinase 4
Nuclear mitogen- and stress-activated protein kinase 2
RSK-like protein kinase
Short name=RLSK

Gene names

Name:	Rps6ka4
Synonyms:	Msk2

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	773 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factor RELA, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors By similarity. Ref.4 Ref.5 Ref.8
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. UniProtKB O75582
Cofactor	Magnesium By similarity. UniProtKB O75582
Enzyme regulation	Activated by phosphorylation at Ser-343, Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by further autophosphorylation of Ser-196, Ser-360 and Ser-365 by the activated C-terminal kinase domain By similarity.
Subunit structure	Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA4 associates with and phosphorylates the NF-kappa-B p65 subunit RELA By similarity.
Subcellular location	Nucleus By similarity UniProtKB O75676.
Post-translational modification	Ser-343 and Thr-568 phosphorylation is required for kinase activity. Ser-343 and Ser-196 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Phosphorylated at Ser-343, Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. Autophosphorylated at Ser-737 and Ser-745 by the N-terminal kinase domain By similarity.
Miscellaneous	Enzyme activity requires the presence of both kinase domains By similarity. UniProtKB O75582
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	Inflammatory response Stress response
Cellular component	Nucleus
Domain	Repeat
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	histone H3-S10 phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB histone H3-S28 phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW interleukin-1-mediated signaling pathway Inferred from electronic annotation. Source: Compara intracellular protein kinase cascade Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of histone acetylation Inferred from electronic annotation. Source: Compara positive regulation of histone phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara regulation of transcription, DNA-dependent Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	cytoplasm Inferred from electronic annotation. Source: Compara nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from sequence or structural similarity. Source: UniProtKB magnesium ion binding Inferred from electronic annotation. Source: InterPro mitogen-activated protein kinase p38 binding Inferred from sequence or structural similarity. Source: UniProtKB protein serine/threonine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Mapk1	P63085	3	EBI-412887,EBI-397697

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 773	773	Ribosomal protein S6 kinase alpha-4		PRO_0000086206
Regions
	Domain	33 – 301	269	Protein kinase 1
	Domain	302 – 371	70	AGC-kinase C-terminal
	Domain	417 – 674	258	Protein kinase 2
	Nucleotide binding	39 – 47	9	ATP By similarity UniProtKB Q15418
	Nucleotide binding	417 – 425	9	ATP By similarity UniProtKB Q15418
Sites
	Active site	161	1	Proton acceptor By similarity UniProtKB Q15418
	Active site	530	1	Proton acceptor By similarity UniProtKB Q15418
	Binding site	65	1	ATP By similarity UniProtKB Q15418
	Binding site	440	1	ATP By similarity UniProtKB Q15418
Amino acid modifications
	Modified residue	196	1	Phosphoserine; by autocatalysis By similarity UniProtKB Q15418
	Modified residue	343	1	Phosphoserine; by MAPK1, MAPK3 and MAPK14 Probable UniProtKB Q15418
	Modified residue	347	1	Phosphoserine Ref.6
	Modified residue	360	1	Phosphoserine; by autocatalysis By similarity UniProtKB Q15418
	Modified residue	365	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	542	1	Phosphothreonine By similarity
	Modified residue	568	1	Phosphothreonine; by MAPK1, MAPK3 and MAPK14 By similarity UniProtKB Q15418
	Modified residue	634	1	Phosphoserine By similarity
	Modified residue	678	1	Phosphoserine By similarity
	Modified residue	687	1	Phosphothreonine; by MAPK1, MAPK3 and MAPK14 By similarity
	Modified residue	737	1	Phosphoserine; by autocatalysis By similarity UniProtKB Q15418
	Modified residue	745	1	Phosphoserine; by autocatalysis Probable
Experimental info
	Sequence conflict	307	1	V → W in AAC67394. Ref.1
	Sequence conflict	343	1	S → P in AAH12964. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q9Z2B9 [UniParc]. Last modified July 27, 2011. Version 2. Checksum: 298DA76E00A9937F	FASTA	773	85,652
	10 20 30 40 50 60 MGDEDEDEGC AVELQITEAN LTGHEEKVSV ENFALLKVLG TGAYGKVFLV RKTGGHDAGK 70 80 90 100 110 120 LYAMKVLRKA ALVQRAKTQE HTRTERSVLE LVRQAPFLVT LHYAFQTDAK LHLILDYVSG 130 140 150 160 170 180 GEMFTHLYQR QYFKEAEVRV YGGEIVLALE HLHKLGIIYR DLKLENVLLD SEGHIVLTDF 190 200 210 220 230 240 GLSKEFLTEE KERTFSFCGT IEYMAPEIIR SKAGHGKAVD WWSLGILLFE LLTGASPFTL 250 260 270 280 290 300 EGERNTQAEV SRRILKCSPP FPLRIGPVAQ DLLQRLLCKD PKKRLGAGPQ GAQEVKSHPF 310 320 330 340 350 360 FQGLDWVALA ARKIPAPFRP QIRSELDVGN FAEEFTRLEP VYSPAGSPPP GDPRIFQGYS 370 380 390 400 410 420 FVAPSILFDH NNAVMADVLQ APGAGYRPGR AAVARSAMMQ DSPFFQQYEL DLREPALGQG 430 440 450 460 470 480 SFSVCRRCRQ RQSGQEFAVK ILSRRLEENT QREVAALRLC QSHPNVVNLH EVLHDQLHTY 490 500 510 520 530 540 LVLELLRGGE LLEHIRKKRL FSESEASQIL RSLVSAVSFM HEEAGVVHRD LKPENILYAD 550 560 570 580 590 600 DTPGAPVKII DFGFARLRPQ SPAEPMQTPC FTLQYAAPEL LAQQGYDESC DLWSLGVILY 610 620 630 640 650 660 MMLSGQVPFQ GASGQGGQSQ AAEIMCKIRE GRFSLDGEAW QGVSEEAKEL VRGLLTVDPA 670 680 690 700 710 720 KRLKLEGLRS SSWLQDGSAR SSPPLRTPDV LESSGPAVRS GLNATFMAFN RGKREGFFLK 730 740 750 760 770 SVENAPLAKR RKQKLRSAAA SRRGSPVPAS SGRLPASAAK GTTRRANGPL SPS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB." Deak M., Clifton A.D., Lucocq J.M., Alessi D.R. EMBO J. 17:4426-4441(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: NOD.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver.
[4]	"MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts." Wiggin G.R., Soloaga A., Foster J.M., Murray-Tait V., Cohen P., Arthur J.S. Mol. Cell. Biol. 22:2871-2881(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF CREB1 AND ATF1.
[5]	"The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation." Duncan E.A., Anest V., Cogswell P., Baldwin A.S. J. Biol. Chem. 281:12521-12525(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HISTONE H3.
[6]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-343 AND SER-347, MASS SPECTROMETRY. Tissue: Liver.
[7]	"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 SER-745, MASS SPECTROMETRY. Tissue: Melanoma.
[8]	"The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling." Ananieva O., Darragh J., Johansen C., Carr J.M., McIlrath J., Park J.M., Wingate A., Monk C.E., Toth R., Santos S.G., Iversen L., Arthur J.S. Nat. Immunol. 9:1028-1036(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF CREB1; ATF1 AND HISTONE H3.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF074714 mRNA. Translation: AAC67394.1. AK154674 mRNA. Translation: BAE32757.1. BC012964 mRNA. Translation: AAH12964.1.
IPI	IPI00131006.
RefSeq	NP_064308.1. NM_019924.1.
UniGene	Mm.20914.
3D structure databases
ProteinModelPortal	Q9Z2B9.
SMR	Q9Z2B9. Positions 12-364, 373-717.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9Z2B9. 1 interaction.
PTM databases
PhosphoSite	Q9Z2B9.
Proteomic databases
PaxDb	Q9Z2B9.
PRIDE	Q9Z2B9.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000025903; ENSMUSP00000025903; ENSMUSG00000024952. ENSMUST00000170516; ENSMUSP00000131581; ENSMUSG00000024952.
GeneID	56613.
KEGG	mmu:56613.
UCSC	uc008gja.1. mouse.
Organism-specific databases
CTD	8986.
MGI	MGI:1930076. Rps6ka4.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00680000099806.
HOGENOM	HOG000233033.
HOVERGEN	HBG108317.
InParanoid	Q3U3M8.
KO	K16510.
OMA	VHHDQLH.
OrthoDB	EOG4VMFDS.
Gene expression databases
Bgee	Q9Z2B9.
CleanEx	MM_RPS6KA4.
Genevestigator	Q9Z2B9.
GermOnline	ENSMUSG00000024952. 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
NextBio	313035.
SOURCE	Search...

Entry information

Entry name

KS6A4_MOUSE

Accession

Primary (citable) accession number: Q9Z2B9
Secondary accession number(s): Q3U3M8, Q91X18

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 24, 2003
Last sequence update:	July 27, 2011
Last modified:	May 1, 2013
This is version 116 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program