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P49760 (CLK2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 146. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Dual specificity protein kinase CLK2

EC=2.7.12.1
Alternative name(s):
CDC-like kinase 2
Gene names
Name:CLK2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length499 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Ref.5 Ref.6 Ref.7 Ref.12

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

5,6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB) inhibits autophosphorylation. TG003 inhibits its kinase activity and affects the regulation of alternative splicing mediated by phosphorylation of SR proteins By similarity.

Subunit structure

Interacts with RBMX. Interacts with AKT1 and UBL5. Ref.8 Ref.13 Ref.15

Subcellular location

Isoform 1: Nucleus. Nucleus speckle. Note: Inhibition of phosphorylation at Ser-142 results in accumulation in the nuclear speckle By similarity. Ref.6

Isoform 2: Nucleus speckle. Note: Co-localizes with serine- and arginine-rich (SR) proteins in the nuclear speckles. Ref.6

Tissue specificity

Endothelial cells. Ref.12

Post-translational modification

Autophosphorylates on all three types of residues. Phosphorylation on Ser-34 and Thr-127 by AKT1 is induced by ionizing radiation or insulin. Phosphorylation plays a critical role in cell proliferation following low dose radiation and prevents cell death following high dose radiation. Phosphorylation at Thr-344 by PKB/AKT2 induces its kinase activity which is required for its stability. The phosphorylation status at Ser-142 influences its subnuclear localization; inhibition of phosphorylation at Ser-142 results in accumulation in the nuclear speckle.

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. Lammer subfamily.

Contains 1 protein kinase domain.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

CLK3P497613EBI-750020,EBI-745579
SNRNP70P086212EBI-750020,EBI-1049228

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P49760-1)

Also known as: Long;

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: P49760-2)

Also known as: Short;

The sequence of this isoform differs from the canonical sequence as follows:
     134-139: QHSSRR → MKSLAP
     140-499: Missing.
Note: Lacks the kinase domain. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Isoform 3 (identifier: P49760-3)

The sequence of this isoform differs from the canonical sequence as follows:
     134-134: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 499499Dual specificity protein kinase CLK2
PRO_0000085868

Regions

Domain163 – 479317Protein kinase
Nucleotide binding169 – 1779ATP By similarity

Sites

Active site2901Proton acceptor By similarity
Binding site1931ATP By similarity

Amino acid modifications

Modified residue341Phosphoserine; by PKB/AKT1 Ref.15
Modified residue981Phosphoserine; by autocatalysis
Modified residue991Phosphotyrosine; by autocatalysis By similarity
Modified residue1271Phosphothreonine; by PKB/AKT1 Ref.15
Modified residue1421Phosphoserine; by autocatalysis Ref.10 Ref.11 Ref.14
Modified residue1531Phosphotyrosine Ref.14
Modified residue3441Phosphothreonine; by PKB/AKT2 By similarity

Natural variations

Alternative sequence134 – 1396QHSSRR → MKSLAP in isoform 2.
VSP_004856
Alternative sequence1341Missing in isoform 3.
VSP_038744
Alternative sequence140 – 499360Missing in isoform 2.
VSP_004857

Secondary structure

........................................................ 499
Helix Strand Turn

Details...

Sequences

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

Last modified October 1, 1996. Version 1.
Checksum: E43BBF3BAD6EF991

FASTA49960,090
        10         20         30         40         50         60 
MPHPRRYHSS ERGSRGSYRE HYRSRKHKRR RSRSWSSSSD RTRRRRREDS YHVRSRSSYD 

        70         80         90        100        110        120 
DRSSDRRVYD RRYCGSYRRN DYSRDRGDAY YDTDYRHSYE YQRENSSYRS QRSSRRKHRR 

       130        140        150        160        170        180 
RRRRSRTFSR SSSQHSSRRA KSVEDDAEGH LIYHVGDWLQ ERYEIVSTLG EGTFGRVVQC 

       190        200        210        220        230        240 
VDHRRGGARV ALKIIKNVEK YKEAARLEIN VLEKINEKDP DNKNLCVQMF DWFDYHGHMC 

       250        260        270        280        290        300 
ISFELLGLST FDFLKDNNYL PYPIHQVRHM AFQLCQAVKF LHDNKLTHTD LKPENILFVN 

       310        320        330        340        350        360 
SDYELTYNLE KKRDERSVKS TAVRVVDFGS ATFDHEHHST IVSTRHYRAP EVILELGWSQ 

       370        380        390        400        410        420 
PCDVWSIGCI IFEYYVGFTL FQTHDNREHL AMMERILGPI PSRMIRKTRK QKYFYRGRLD 

       430        440        450        460        470        480 
WDENTSAGRY VRENCKPLRR YLTSEAEEHH QLFDLIESML EYEPAKRLTL GEALQHPFFA 

       490 
RLRAEPPNKL WDSSRDISR 

« Hide

Isoform 2 (Short) [UniParc].

Checksum: CC9C9C63B3B07667
Show »

FASTA13917,569
Isoform 3 [UniParc].

Checksum: 0A21FC66FD22DBC6
Show »

FASTA49859,962

References

« Hide 'large scale' references
[1]"Characterization by cDNA cloning of two new human protein kinases. Evidence by sequence comparison of a new family of mammalian protein kinases."
Hanes J.J., der Kammer H., Klaudiny J.J., Scheit K.H.
J. Mol. Biol. 244:665-672(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
[2]"Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: implications for Gaucher disease."
Winfield S.L., Tayebi N., Martin B.M., Ginns E.I., Sidransky E.
Genome Res. 7:1020-1026(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[3]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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] (ISOFORMS 1 AND 3).
Tissue: Lung and Ovary.
[5]"Activity and autophosphorylation of LAMMER protein kinases."
Lee K., Du C., Horn M., Rabinow L.
J. Biol. Chem. 271:27299-27303(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"The Clk2 and Clk3 dual-specificity protein kinases regulate the intranuclear distribution of SR proteins and influence pre-mRNA splicing."
Duncan P.I., Stojdl D.F., Marius R.M., Scheit K.H., Bell J.C.
Exp. Cell Res. 241:300-308(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION.
[7]"The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B."
Moeslein F.M., Myers M.P., Landreth G.E.
J. Biol. Chem. 274:26697-26704(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"Beacon interacts with cdc2/cdc28-like kinases."
Kantham L., Kerr-Bayles L., Godde N., Quick M., Webb R., Sunderland T., Bond J., Walder K., Augert G., Collier G.
Biochem. Biophys. Res. Commun. 304:125-129(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH UBL5.
[9]"An unappreciated role for RNA surveillance."
Hillman R.T., Green R.E., Brenner S.E.
Genome Biol. 5:R8.1-R8.16(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
[10]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-142, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[11]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-142, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[12]"Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor in human endothelial cells."
Eisenreich A., Bogdanov V.Y., Zakrzewicz A., Pries A., Antoniak S., Poller W., Schultheiss H.P., Rauch U.
Circ. Res. 104:589-599(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ALTERNATIVE SPLICING, TISSUE SPECIFICITY.
[13]"Heterogeneous nuclear ribonucleoprotein G regulates splice site selection by binding to CC(A/C)-rich regions in pre-mRNA."
Heinrich B., Zhang Z., Raitskin O., Hiller M., Benderska N., Hartmann A.M., Bracco L., Elliott D., Ben-Ari S., Soreq H., Sperling J., Sperling R., Stamm S.
J. Biol. Chem. 284:14303-14315(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RBMX.
[14]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-142 AND TYR-153, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]"Phosphorylation of CLK2 at serine 34 and threonine 127 by AKT controls cell survival after ionizing radiation."
Nam S.Y., Seo H.H., Park H.S., An S., Kim J.Y., Yang K.H., Kim C.S., Jeong M., Jin Y.W.
J. Biol. Chem. 285:31157-31163(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-34 AND THR-127, INTERACTION WITH AKT1.
[16]"Structure of human cdc2-like kinase 2 (clk2)."
Structural genomics consortium (SGC)
Submitted (AUG-2010) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.89 ANGSTROMS) OF 135-496.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L29218 mRNA. Translation: AAA61482.1.
L29216 mRNA. Translation: AAA61481.1.
AF023268 Genomic DNA. Translation: AAC51817.1.
AL713999 Genomic DNA. Translation: CAI95098.1.
BC014067 mRNA. Translation: AAH14067.1.
BC053603 mRNA. Translation: AAH53603.1.
PIRS53637.
S53638.
RefSeqNP_003984.2. NM_003993.2.
XP_005244933.1. XM_005244876.1.
XP_005276799.1. XM_005276742.1.
UniGeneHs.73986.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3NR9X-ray2.89A/B/C135-496[»]
ProteinModelPortalP49760.
SMRP49760. Positions 136-482.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107607. 39 interactions.
IntActP49760. 30 interactions.
MINTMINT-1683264.
STRING9606.ENSP00000354856.

Chemistry

BindingDBP49760.
ChEMBLCHEMBL4225.
GuidetoPHARMACOLOGY1991.

PTM databases

PhosphoSiteP49760.

Polymorphism databases

DMDM1705919.

Proteomic databases

PaxDbP49760.
PRIDEP49760.

Protocols and materials databases

DNASU1196.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000361168; ENSP00000354856; ENSG00000176444. [P49760-3]
ENST00000368361; ENSP00000357345; ENSG00000176444. [P49760-1]
ENST00000536801; ENSP00000441023; ENSG00000176444. [P49760-1]
ENST00000572269; ENSP00000459461; ENSG00000261893. [P49760-3]
ENST00000574445; ENSP00000460443; ENSG00000261893. [P49760-1]
GeneID1196.
KEGGhsa:1196.
UCSCuc001fjw.3. human. [P49760-3]
uc001fjx.3. human. [P49760-1]

Organism-specific databases

CTD1196.
GeneCardsGC01M155232.
H-InvDBHIX0001112.
HGNCHGNC:2069. CLK2.
HPAHPA055366.
MIM602989. gene.
neXtProtNX_P49760.
PharmGKBPA26595.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000203417.
HOVERGENHBG107720.
InParanoidP49760.
KOK08823.
OMAYEPSKRL.
PhylomeDBP49760.
TreeFamTF101041.

Enzyme and pathway databases

BRENDA2.7.12.1. 2681.
SignaLinkP49760.

Gene expression databases

ArrayExpressP49760.
BgeeP49760.
CleanExHS_CLK2.
GenevestigatorP49760.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSCLK2. human.
EvolutionaryTraceP49760.
GeneWikiCLK2.
GenomeRNAi1196.
NextBio4940.
PROP49760.
SOURCESearch...

Entry information

Entry nameCLK2_HUMAN
AccessionPrimary (citable) accession number: P49760
Secondary accession number(s): B1AVS9, B5MBX6, Q96CQ0
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: April 16, 2014
This is version 146 of the entry and version 1 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 chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM