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Q6VAB6 (KSR2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified May 14, 2014. Version 95. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Kinase suppressor of Ras 2

Short name=hKSR2
EC=2.7.11.1
Gene names
Name:KSR2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length950 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Location-regulated scaffold connecting MEK to RAF. Has very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency (in vitro). Interaction with BRAF enhances KSR2-mediated phosphorylation of MAP2K1 (in vitro). Blocks MAP3K8 kinase activity and MAP3K8-mediated signaling. Acts as a negative regulator of MAP3K3-mediated activation of ERK, JNK and NF-kappa-B pathways, inhibiting MAP3K3-mediated interleukin-8 production. Ref.3 Ref.5 Ref.6

Catalytic activity

ATP + a protein = ADP + a phosphoprotein. Ref.6

Enzyme regulation

Kinase activity is inhibited by ASC24. Ref.6

Subunit structure

Interacts with MAP2K1, forming a heterodimer that can dimerize to form a heterotetramer. Interacts with MAP3K8, MAPK, RAS and RAF. Interacts with BRAF; this increases the low intrinsic protein kinase activity of KSR2. Ref.3 Ref.6

Subcellular location

Cytoplasm By similarity. Membrane; Peripheral membrane protein By similarity.

Tissue specificity

Mainly expressed in brain and kidney. Ref.3

Domain

The protein kinase domain is predicted to be catalytically inactive and seems to have very low intrinsic kinase activity. This low kinase activity can be increased by interaction with BRAF.

Post-translational modification

Phosphorylated on Ser-474 by MARK3 By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Contains 1 phorbol-ester/DAG-type zinc finger.

Contains 1 protein kinase domain.

Caution

KSR2 binds ATP and has very low in vitro protein kinase activity; the physiological relevance of this activity is unknown. KSR2 is proposed to be in an inactive conformation by itself or in complex with MAP2K1. Interaction with BRAF is proposed to induce a conformation change that increases the low intrinsic kinase activity (Ref.6).

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q6VAB6-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q6VAB6-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-303: Missing.
     304-329: GFTALHRSKSHEFQLGHRVDEAHTPK → MYNKKAKMEPNASESAIPARRQRQPR
     740-742: SLC → RPV
     743-950: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 950950Kinase suppressor of Ras 2
PRO_0000086231

Regions

Domain666 – 931266Protein kinase
Zinc finger412 – 45645Phorbol-ester/DAG-type
Nucleotide binding672 – 6809ATP
Compositional bias181 – 293113Pro-rich
Compositional bias510 – 55041Pro-rich

Sites

Active site7861Proton donor/acceptor Probable
Metal binding4131Zinc 1 By similarity
Metal binding4251Zinc 2 By similarity
Metal binding4281Zinc 2 By similarity
Metal binding4381Zinc 1 By similarity
Metal binding4411Zinc 1 By similarity
Metal binding4461Zinc 2 By similarity
Metal binding4491Zinc 2 By similarity
Metal binding4561Zinc 1 By similarity
Binding site7881ATP Probable
Binding site8031ATP Probable

Amino acid modifications

Modified residue4741Phosphoserine; by MARK3 By similarity

Natural variations

Alternative sequence1 – 303303Missing in isoform 2.
VSP_012234
Alternative sequence304 – 32926GFTAL…AHTPK → MYNKKAKMEPNASESAIPAR RQRQPR in isoform 2.
VSP_012235
Alternative sequence740 – 7423SLC → RPV in isoform 2.
VSP_012236
Alternative sequence743 – 950208Missing in isoform 2.
VSP_012237
Natural variant6761R → S in a lung adenocarcinoma sample; somatic mutation. Ref.7
VAR_040659

Experimental info

Mutagenesis7181R → H: Impairs formation of heterotetramers with MAP2K1, but not the formation of heterodimers. Ref.6
Mutagenesis7861D → A: Loss of kinase activity. Ref.6
Mutagenesis8791A → L: Impairs MAP2K1 binding. Ref.6

Secondary structure

.................................... 950
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified May 29, 2007. Version 2.
Checksum: DFBC20F4E71077AD

FASTA950107,632
        10         20         30         40         50         60 
MDEENMTKSE EQQPLSLQKA LQQCELVQNM IDLSISNLEG LRTKCATSND LTQKEIRTLE 

        70         80         90        100        110        120 
SKLVKYFSRQ LSCKKKVALQ ERNAELDGFP QLRHWFRIVD VRKEVLEEIS PGQLSLEDLL 

       130        140        150        160        170        180 
EMTDEQVCET VEKYGANREE CARLNASLSC LRNVHMSGGN LSKQDWTIQW PTTETGKENN 

       190        200        210        220        230        240 
PVCPPEPTPW IRTHLSQSPR VPSKCVQHYC HTSPTPGAPV YTHVDRLTVD AYPGLCPPPP 

       250        260        270        280        290        300 
LESGHRSLPP SPRQRHAVRT PPRTPNIVTT VTPPGTPPMR KKNKLKPPGT PPPSSRKLIH 

       310        320        330        340        350        360 
LIPGFTALHR SKSHEFQLGH RVDEAHTPKA KKKSKPLNLK IHSSVGSCEN IPSQQRSPLL 

       370        380        390        400        410        420 
SERSLRSFFV GHAPFLPSTP PVHTEANFSA NTLSVPRWSP QIPRRDLGNS IKHRFSTKYW 

       430        440        450        460        470        480 
MSQTCTVCGK GMLFGLKCKN CKLKCHNKCT KEAPPCHLLI IHRGDPARLV RTESVPCDIN 

       490        500        510        520        530        540 
NPLRKPPRYS DLHISQTLPK TNKINKDHIP VPYQPDSSSN PSSTTSSTPS SPAPPLPPSA 

       550        560        570        580        590        600 
TPPSPLHPSP QCTRQQKNFN LPASHYYKYK QQFIFPDVVP VPETPTRAPQ VILHPVTSNP 

       610        620        630        640        650        660 
ILEGNPLLQI EVEPTSENEE VHDEAEESED DFEEMNLSLL SARSFPRKAS QTSIFLQEWD 

       670        680        690        700        710        720 
IPFEQLEIGE LIGKGRFGQV YHGRWHGEVA IRLIDIERDN EDQLKAFKRE VMAYRQTRHE 

       730        740        750        760        770        780 
NVVLFMGACM SPPHLAIITS LCKGRTLYSV VRDAKIVLDV NKTRQIAQEI VKGMGYLHAK 

       790        800        810        820        830        840 
GILHKDLKSK NVFYDNGKVV ITDFGLFSIS GVLQAGRRED KLRIQNGWLC HLAPEIIRQL 

       850        860        870        880        890        900 
SPDTEEDKLP FSKHSDVFAL GTIWYELHAR EWPFKTQPAE AIIWQMGTGM KPNLSQIGMG 

       910        920        930        940        950 
KEISDILLFC WAFEQEERPT FTKLMDMLEK LPKRNRRLSH PGHFWKSAEL 

« Hide

Isoform 2 [UniParc].

Checksum: A5D6F1DEAFDA51FC
Show »

FASTA43949,607

References

« Hide 'large scale' references
[1]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Testis.
[2]"The finished DNA sequence of human chromosome 12."
Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. expand/collapse author list , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A.
Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling."
Channavajhala P.L., Wu L., Cuozzo J.W., Hall J.P., Liu W., Lin L.-L., Zhang Y.
J. Biol. Chem. 278:47089-47097(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 122-950 (ISOFORM 1), FUNCTION, INTERACTION WITH MAP2K; RAS; RAF; MAPK AND MAP3K8, TISSUE SPECIFICITY.
Tissue: Testis.
[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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 122-950 (ISOFORM 1).
[5]"hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappaB pathways in inflammation."
Channavajhala P.L., Rao V.R., Spaulding V., Lin L.-L., Zhang Y.G.
Biochem. Biophys. Res. Commun. 334:1214-1218(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK."
Brennan D.F., Dar A.C., Hertz N.T., Chao W.C., Burlingame A.L., Shokat K.M., Barford D.
Nature 472:366-369(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.46 ANGSTROMS) OF 634-950 OF MUTANT ALA-786 IN COMPLEX WITH ATP AND MAP2K1, FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION, SUBUNIT, INTERACTION WITH BRAF AND MAP2K1, ACTIVE SITE, MUTAGENESIS OF ARG-718; ASP-786 AND ALA-879.
[7]"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. expand/collapse author list , 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] [Europe PMC] [Abstract]
Cited for: VARIANT [LARGE SCALE ANALYSIS] SER-676.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AK098831 mRNA. Translation: BAC05426.1.
AC073864 Genomic DNA. No translation available.
AC079127 Genomic DNA. No translation available.
AC084291 Genomic DNA. No translation available.
AC092936 Genomic DNA. No translation available.
AY345972 mRNA. Translation: AAQ24226.1.
BC107106 mRNA. Translation: AAI07107.1.
BC107107 mRNA. Translation: AAI07108.1.
BC127603 mRNA. Translation: AAI27604.1.
RefSeqNP_775869.3. NM_173598.4.
UniGeneHs.375836.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2Y4IX-ray3.46B634-950[»]
ProteinModelPortalQ6VAB6.
SMRQ6VAB6. Positions 16-154, 626-931.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid129567. 5 interactions.
DIPDIP-59195N.
IntActQ6VAB6. 2 interactions.
MINTMINT-8397064.
STRING9606.ENSP00000339952.

PTM databases

PhosphoSiteQ6VAB6.

Polymorphism databases

DMDM148886599.

Proteomic databases

PaxDbQ6VAB6.
PRIDEQ6VAB6.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000339824; ENSP00000339952; ENSG00000171435. [Q6VAB6-1]
GeneID283455.
KEGGhsa:283455.
UCSCuc001two.2. human. [Q6VAB6-1]

Organism-specific databases

CTD283455.
GeneCardsGC12M117890.
H-InvDBHIX0018992.
HGNCHGNC:18610. KSR2.
HPAHPA035536.
MIM610737. gene.
neXtProtNX_Q6VAB6.
PharmGKBPA134914125.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000113263.
HOVERGENHBG052293.
InParanoidQ6VAB6.
OMAFCWAYEQ.
OrthoDBEOG7BP81Z.
PhylomeDBQ6VAB6.
TreeFamTF317006.

Enzyme and pathway databases

SignaLinkQ6VAB6.

Gene expression databases

ArrayExpressQ6VAB6.
BgeeQ6VAB6.
CleanExHS_KSR2.
GenevestigatorQ6VAB6.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR025561. KSR_SAM-like_dom.
IPR002219. Prot_Kinase_C-like_PE/DAG-bd.
IPR000719. Prot_kinase_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF13543. KSR1-SAM. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SMARTSM00109. C1. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS00479. ZF_DAG_PE_1. 1 hit.
PS50081. ZF_DAG_PE_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSKSR2. human.
GenomeRNAi283455.
NextBio93924.
PROQ6VAB6.
SOURCESearch...

Entry information

Entry nameKSR2_HUMAN
AccessionPrimary (citable) accession number: Q6VAB6
Secondary accession number(s): A0PJT2, Q3B828, Q8N775
Entry history
Integrated into UniProtKB/Swiss-Prot: December 21, 2004
Last sequence update: May 29, 2007
Last modified: May 14, 2014
This is version 95 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM