Reviewed, UniProtKB/Swiss-Prot O75582 (KS6A5_HUMAN)

Names and origin

Protein names

Recommended name:
    Ribosomal protein S6 kinase alpha-5
    EC=2.7.11.1
Alternative name(s):
    Nuclear mitogen- and stress-activated protein kinase 1
    90 kDa ribosomal protein S6 kinase 5
    RSK-like protein kinase
      Short name=RSKL

Gene names

Name:	RPS6KA5
Synonyms:	MSK1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	802 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Serine/threonine kinase required for the mitogen or stress-induced phosphorylation of the transcription factors CREB (cAMP response element-binding protein) and ATF1 (activating transcription factor-1). Essential role in the control of RELA transcriptional activity in response to TNF. Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and epidemal growth-factor (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 14 (HMG-14). Ref.1 Ref.2 Ref.5 Ref.6 Ref.7 Ref.8
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.1 Ref.2 Ref.6
Cofactor	Magnesium. Ref.1 Ref.2 Ref.6
Enzyme regulation	Appears to be activated by multiple phosphorylations on threonine and serine residues. ERK1/2 and MAPK14/p38-alpha may play a role in this process. Ref.1 Ref.9 UniProtKB Q15418 UniProtKB O75676
Subunit structure	Forms a complex with either ERK1 or ERK2 in quiescent cells which transiently dissociates following mitogenic stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA5 associates with and phosphorylates the NF-kappa-B p65 subunit RELA. Ref.6 UniProtKB Q15418 UniProtKB O75676
Subcellular location	Nucleus. Cytoplasm. Note: Predominantly nuclear. Partially cytoplasmic. Ref.1
Tissue specificity	Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver. Ref.1 Ref.2
Post-translational modification	Ser-376 and Thr-581 phosphorylation is required for kinase activity. Ser-376 and Ser-212 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Ref.7 Ref.8 Ref.9
Miscellaneous	Enzyme activity requires the presence of both kinase domains. Ref.1
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
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Domain	Repeat
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	epidermal growth factor receptor signaling pathway Ref.2 Traceable author statement. Source: UniProtKB histone phosphorylation Ref.2 Inferred from direct assay. Source: UniProtKB protein kinase cascade Ref.1 Inferred from direct assay. Source: UniProtKB regulation of transcription, DNA-dependent Ref.1 Inferred from direct assay. Source: UniProtKB response to chemical stimulus Ref.2 Inferred from expression pattern. Source: UniProtKB response to external stimulus Ref.2 Inferred from expression pattern. Source: UniProtKB response to stress Ref.2 Inferred from expression pattern. Source: UniProtKB
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Ref.1 Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Ref.1 Inferred from direct assay. Source: UniProtKB magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.6 Inferred from physical interaction. Source: IntAct protein serine/threonine kinase activity Ref.1 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
RELA	Q04206	1	EBI-73869,EBI-73886

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 802

802

Ribosomal protein S6 kinase alpha-5

PRO_0000086207

Regions

Domain

49 – 318

270

Protein kinase 1

Domain

319 – 387

69

AGC-kinase C-terminal

Domain

426 – 687

262

Protein kinase 2

Nucleotide binding

55 – 63

9

ATP By similarity UniProtKB Q15418

Nucleotide binding

432 – 440

9

ATP By similarity UniProtKB Q15418

Sites

Active site

177

1

Proton acceptor By similarity UniProtKB Q15418

Active site

544

1

Proton acceptor By similarity UniProtKB Q15418

Binding site

81

1

ATP By similarity UniProtKB Q15418

Binding site

455

1

ATP By similarity UniProtKB Q15418

Amino acid modifications

Modified residue

212

1

Phosphoserine; by autocatalysis Ref.9 UniProtKB Q15418

Modified residue

360

1

Phosphoserine; by MAPK3, MAPK1 and MAPK14 UniProtKB Q15418

Modified residue

376

1

Phosphoserine; by autocatalysis Ref.9 UniProtKB Q15418

Modified residue

381

1

Phosphoserine; by autocatalysis Ref.9

Modified residue

581

1

Phosphothreonine; by MAPK1, MAPK3 and MAPK14 UniProtKB Q15418

Modified residue

750

1

Phosphoserine; by autocatalysis Ref.9 UniProtKB Q15418

Modified residue

752

1

Phosphoserine; by autocatalysis Ref.9

Modified residue

758

1

Phosphoserine; by autocatalysis Ref.9

Natural variations

Natural variant

190

1

H → R: dbSNP rs34699345.

VAR_051634

Natural variant

554

1

D → N Ref.11

VAR_040634

Natural variant

574

1

P → L Ref.11

VAR_040635

Natural variant

599

1

Y → C Ref.11

VAR_040636

Experimental info

Mutagenesis

195

1

D → A: Loss of kinase activity. Ref.1

Mutagenesis

212

1

S → A: Inactives the N-terminal kinase domain. Ref.9

Mutagenesis

360

1

S → A: Decreases kinase activity by 60% in response to PMA and UV-C. Ref.9

Mutagenesis

376

1

S → A: Loss of kinase activity, and decreases the phosphorylation of S-360 and T-581. Ref.9

Mutagenesis

565

1

D → A: Loss of kinase activity. Ref.1

Mutagenesis

581

1

T → A: Loss of kinase activity, and blocks phosphorylation of S-212; S-376 and S-381 in response to PMA and UV-C. Ref.9

Sequence conflict

452 – 453

2

FA → LQ in AAC69577. Ref.3

Sequence conflict

508 – 511

4

ERIK → DALR in AAC69577. Ref.3

Sequence conflict

532

1

V → L in AAC69577. Ref.3

Sequence conflict

538

1

V → L in AAC69577. Ref.3

Sequence conflict

549

1

N → V in AAH17187. Ref.4

Sequence conflict

588 – 590

3

YAA → SCR in AAC69577. Ref.3

Sequence conflict

757 – 758

2

SS → RG in AAC69577. Ref.3

Sequence conflict

801 – 802

2

VA → ELRHGRSDQ in AAC69577. Ref.3

Secondary structure

1

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802

Helix Strand Turn

Details...

Beta strand

26 – 31

6

Helix

46 – 48

3

Beta strand

49 – 57

9

Turn

58 – 60

3

Beta strand

61 – 68

8

Turn

72 – 75

4

Beta strand

77 – 94

18

Helix

95 – 97

3

Helix

101 – 109

9

Beta strand

117 – 123

7

Beta strand

126 – 131

6

Helix

139 – 146

8

Helix

151 – 170

20

Helix

180 – 182

3

Beta strand

183 – 185

3

Beta strand

191 – 194

4

Beta strand

196 – 201

6

Helix

204 – 210

7

Helix

212 – 214

3

Helix

222 – 225

4

Helix

235 – 250

16

Helix

264 – 273

10

Helix

284 – 293

10

Helix

298 – 300

3

Turn

306 – 308

3

Helix

309 – 313

5

Helix

316 – 318

3

Helix

323 – 327

5

Sequences

	Sequence		Length	Mass (Da)
	O75582-1 [UniParc]. Last modified November 1, 1998. Version 1. Checksum: 76C27D0F6639BFA4	FASTA	802	89,865
	10 20 30 40 50 60 MEEEGGSSGG AAGTSADGGD GGEQLLTVKH ELRTANLTGH AEKVGIENFE LLKVLGTGAY 70 80 90 100 110 120 GKVFLVRKIS GHDTGKLYAM KVLKKATIVQ KAKTTEHTRT ERQVLEHIRQ SPFLVTLHYA 130 140 150 160 170 180 FQTETKLHLI LDYINGGELF THLSQRERFT EHEVQIYVGE IVLALEHLHK LGIIYRDIKL 190 200 210 220 230 240 ENILLDSNGH VVLTDFGLSK EFVADETERA YSFCGTIEYM APDIVRGGDS GHDKAVDWWS 250 260 270 280 290 300 LGVLMYELLT GASPFTVDGE KNSQAEISRR ILKSEPPYPQ EMSALAKDLI QRLLMKDPKK 310 320 330 340 350 360 RLGCGPRDAD EIKEHLFFQK INWDDLAAKK VPAPFKPVIR DELDVSNFAE EFTEMDPTYS 370 380 390 400 410 420 PAALPQSSEK LFQGYSFVAP SILFKRNAAV IDPLQFHMGV ERPGVTNVAR SAMMKDSPFY 430 440 450 460 470 480 QHYDLDLKDK PLGEGSFSIC RKCVHKKSNQ AFAVKIISKR MEANTQKEIT ALKLCEGHPN 490 500 510 520 530 540 IVKLHEVFHD QLHTFLVMEL LNGGELFERI KKKKHFSETE ASYIMRKLVS AVSHMHDVGV 550 560 570 580 590 600 VHRDLKPENL LFTDENDNLE IKIIDFGFAR LKPPDNQPLK TPCFTLHYAA PELLNQNGYD 610 620 630 640 650 660 ESCDLWSLGV ILYTMLSGQV PFQSHDRSLT CTSAVEIMKK IKKGDFSFEG EAWKNVSQEA 670 680 690 700 710 720 KDLIQGLLTV DPNKRLKMSG LRYNEWLQDG SQLSSNPLMT PDILGSSGAA VHTCVKATFH 730 740 750 760 770 780 AFNKYKREGF CLQNVDKAPL AKRRKMKKTS TSTETRSSSS ESSHSSSSHS HGKTTPTKTL 790 800 QPSNPADSNN PETLFQFSDS VA

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: 9687510] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, MUTAGENESIS OF ASP-195 AND ASP-565. Tissue: Pancreas.
[2]	"Cloning and characterization of RLPK, a novel RSK-related protein kinase." New L., Zhao M., Li Y., Bassett W.W., Feng Y., Ludwig S., Padova F.D., Gram H., Han J. J. Biol. Chem. 274:1026-1032(1999) [PubMed: 9873047] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY. Tissue: Placenta.
[3]	"Assignment of a member of the ribosomal protein S6 kinase family, RPS6KA5, to human chromosome 14q31-q32.1 by radiation hybrid mapping." Jiang C., Yu L., Tu Q., Zhao Y., Zhang H., Zhao S. Cytogenet. Cell Genet. 87:261-262(1999) [PubMed: 10702687] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL LOCATION.
[4]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-549. Tissue: Placenta.
[5]	"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: 11909979] [Abstract] Cited for: FUNCTION.
[6]	"Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1)." Vermeulen L., De Wilde G., Van Damme P., Vanden Berghe W., Haegeman G. EMBO J. 22:1313-1324(2003) [PubMed: 12628924] [Abstract] Cited for: FUNCTION, INTERACTION WITH RELA.
[7]	"MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14." Soloaga A., Thomson S., Wiggin G.R., Rampersaud N., Dyson M.H., Hazzalin C.A., Mahadevan L.C., Arthur J.S. EMBO J. 22:2788-2797(2003) [PubMed: 12773393] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HISTONE H3 AND HMG14.
[8]	"Phosphorylation of histone H2A inhibits transcription on chromatin templates." Zhang Y., Griffin K., Mondal N., Parvin J.D. J. Biol. Chem. 279:21866-21872(2004) [PubMed: 15010469] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HISTONE H2A.
[9]	"MSK1 activity is controlled by multiple phosphorylation sites." McCoy C.E., Campbell D.G., Deak M., Bloomberg G.B., Arthur J.S.C. Biochem. J. 387:507-517(2005) [PubMed: 15568999] [Abstract] Cited for: ENZYME REGULATION, PHOSPHORYLATION AT SER-212; SER-376; SER-381; SER-750; SER-752 AND SER-758, MUTAGENESIS OF SER-212; SER-360; SER-376 AND THR-581.
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASN-554; LEU-574 AND CYS-599.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF074393 mRNA. Translation: AAC31171.1.
AF080000 mRNA. Translation: AAD23915.1.
AF090421 mRNA. Translation: AAC69577.1.
BC017187 mRNA. Translation: AAH17187.1.

IPI

IPI00335101.

PIR

T13149.

RefSeq

NP_004746.2.
NP_872198.1.

UniGene

Hs.510225

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1VZO	X-ray	1.80	A	2-348	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

O75582. 1 interaction.

PTM databases

PhosphoSite

O75582.

Proteomic databases

PRIDE

O75582.

Genome annotation databases

Ensembl

ENSG00000100784. Homo sapiens. [Contig view]

GeneID

9252.

KEGG

hsa:9252.

Organism-specific databases

GeneCards

GC14M090406.

H-InvDB

HIX0020495.

HGNC

HGNC:10434. RPS6KA5.

HPA

HPA001274.

MIM

603607. gene.

PharmGKB

PA34849.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O75582.

HOVERGEN

O75582.

OMA

O75582. DSGHDKA.

Enzyme and pathway databases

BRENDA

2.7.11.1. 247.

Pathway_Interaction_DB

lpa4_pathway. LPA4-mediated signaling events.
p38alphabetadownstreampathway. Signaling mediated by p38-alpha and p38-beta.
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_11061. Signalling by NGF.

Gene expression databases

ArrayExpress

O75582.

Bgee

O75582.

CleanEx

HS_RPS6KA5.

GermOnline

ENSG00000100784. Homo sapiens.

Family and domain databases

InterPro

IPR000961. AGC-kinase_C.
IPR017892. Pkinase_C.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR016239. Ribosomal_S6_kinase_II.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]

Pfam

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

PIRSF

PIRSF000606. Ribsml_S6_kin_2. 1 hit.

ProDom

PD000001. Prot_kinase. 2 hits.
[Graphical view] [Entries sharing at least one domain]

SMART

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

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 Resources

NextBio

34679.

SOURCE

Search...

Entry information

Entry name

KS6A5_HUMAN

Accession

Primary (citable) accession number: O75582
Secondary accession number(s): O95316, Q96AF7

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 24, 2003
Last sequence update:	November 1, 1998
Last modified:	June 16, 2009
This is version 92 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)