Reviewed, UniProtKB/Swiss-Prot P41240 (CSK_HUMAN)

Names and origin

Protein names

Recommended name:
    Tyrosine-protein kinase CSK
    EC=2.7.10.2
Alternative name(s):
    C-SRC kinase
    Protein-tyrosine kinase CYL

Gene names

Name:

CSK

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

General annotation (Comments)

Function	Specifically phosphorylates 'Tyr-504' on LCK, which acts as a negative regulatory site. Can also act on the LYN and FYN kinases.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Interacts with PTPN8 By similarity. Interacts with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1.
Subcellular location	Cytoplasm By similarity. Cell membrane By similarity. Note: Mainly cytoplasmic, also present in lipid rafts By similarity.
Tissue specificity	Expressed in lung and macrophages. Ref.3
Post-translational modification	Autophosphorylation of Tyr-304 occurs only at abnormally high CSK concentrations in vitro.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. CSK subfamily. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Polymorphism
Domain	SH2 domain SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	protein amino acid phosphorylation Ref.1 Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Traceable author statement. Source: HGNC
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC protein C-terminus binding Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
PTPRB	P23467	1	EBI-1380630,EBI-1265766
PTPRC	P08575	1	EBI-1380630,EBI-1341
PTPRG	P23470	1	EBI-1380630,EBI-2258115
PTPRJ	Q12913	1	EBI-1380630,EBI-2264500
PTPRK	Q15262	1	EBI-1380630,EBI-474052
PTPRO	Q16827	1	EBI-1380630,EBI-723739
PTPRZ1	P23471	1	EBI-1380630,EBI-2263175
SRC	P00523	3	EBI-1380630,EBI-848039	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 450

450

Tyrosine-protein kinase CSK

PRO_0000088070

Regions

Domain

9 – 70

62

SH3

Domain

82 – 171

90

SH2

Domain

195 – 449

255

Protein kinase

Nucleotide binding

201 – 209

9

ATP By similarity

Region

9 – 70

62

Interaction with PTPN8 By similarity

Sites

Active site

314

1

Proton acceptor By similarity

Binding site

222

1

ATP By similarity

Amino acid modifications

Modified residue

184

1

Phosphotyrosine Ref.8 Ref.13

Modified residue

304

1

Phosphotyrosine; by autocatalysis Ref.8

Modified residue

416

1

Phosphotyrosine; by autocatalysis By similarity

Natural variations

Natural variant

45

1

P → L Ref.16

VAR_041678

Natural variant

287

1

G → D: dbSNP rs34866753. Ref.6

VAR_025203

Natural variant

398

1

R → Q Ref.6

VAR_025204

Natural variant

442

1

H → R Ref.6

VAR_025205

Experimental info

Mutagenesis

184

1

Y → F: Abolishes phosphorylation. Ref.8

Mutagenesis

304

1

Y → F: Decreases activity by two-thirds and alters conformation. Ref.8

Secondary structure

1

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450

Helix Strand Turn

Details...

Beta strand

12 – 18

7

Beta strand

35 – 41

7

Beta strand

47 – 51

5

Beta strand

57 – 61

5

Beta strand

64 – 66

3

Helix

192 – 194

3

Beta strand

195 – 203

9

Beta strand

208 – 214

7

Beta strand

217 – 223

7

Helix

231 – 235

5

Helix

237 – 240

4

Beta strand

251 – 255

5

Beta strand

263 – 266

4

Helix

274 – 285

12

Helix

288 – 307

20

Helix

317 – 319

3

Beta strand

320 – 322

3

Beta strand

328 – 330

3

Turn

350 – 352

3

Helix

355 – 360

6

Helix

365 – 380

16

Helix

392 – 394

3

Helix

395 – 399

5

Turn

400 – 402

3

Helix

413 – 422

10

Helix

427 – 429

3

Helix

433 – 446

14

Sequences

	Sequence		Length	Mass (Da)
	P41240-1 [UniParc]. Last modified February 1, 1995. Version 1. Checksum: 431023A88C54E00C	FASTA	450	50,704
	10 20 30 40 50 60 MSAIQAAWPS GTECIAKYNF HGTAEQDLPF CKGDVLTIVA VTKDPNWYKA KNKVGREGII 70 80 90 100 110 120 PANYVQKREG VKAGTKLSLM PWFHGKITRE QAERLLYPPE TGLFLVREST NYPGDYTLCV 130 140 150 160 170 180 SCDGKVEHYR IMYHASKLSI DEEVYFENLM QLVEHYTSDA DGLCTRLIKP KVMEGTVAAQ 190 200 210 220 230 240 DEFYRSGWAL NMKELKLLQT IGKGEFGDVM LGDYRGNKVA VKCIKNDATA QAFLAEASVM 250 260 270 280 290 300 TQLRHSNLVQ LLGVIVEEKG GLYIVTEYMA KGSLVDYLRS RGRSVLGGDC LLKFSLDVCE 310 320 330 340 350 360 AMEYLEGNNF VHRDLAARNV LVSEDNVAKV SDFGLTKEAS STQDTGKLPV KWTAPEALRE 370 380 390 400 410 420 KKFSTKSDVW SFGILLWEIY SFGRVPYPRI PLKDVVPRVE KGYKMDAPDG CPPAVYEVMK 430 440 450 NCWHLDAAMR PSFLQLREQL EHIKTHELHL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"CYL encodes a putative cytoplasmic tyrosine kinase lacking the conserved tyrosine autophosphorylation site (Y416src)." Partanen J., Armstrong E., Bergman M., Maekelae T.P., Hirvonen H., Huebner K., Alitalo K. Oncogene 6:2013-2018(1991) [PubMed: 1945408] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Two additional protein-tyrosine kinases expressed in human lung: fourth member of the fibroblast growth factor receptor family and an intracellular protein-tyrosine kinase." Braeuninger A., Holtrich U., Strebhardt K., Ruebsamen-Waigmann H. Proc. Natl. Acad. Sci. U.S.A. 88:10411-10415(1991) [PubMed: 1720539] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lung.
[3]	"Isolation and characterization of a human gene that encodes a new subclass of protein tyrosine kinases." Brauninger A., Holtrich U., Strebhardt K., Rubsamen-Waigmann H. Gene 110:205-211(1992) [PubMed: 1371489] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY.
[4]	"Characterization of the human CSK locus." Braeuninger A., Karn T., Strebhardt K., Ruebsamen-Waigmann H. Oncogene 8:1365-1369(1993) [PubMed: 7683131] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[6]	NIEHS SNPs program Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ASP-287; GLN-398 AND ARG-442.
[7]	"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]. Tissue: Brain and Uterus.
[8]	"Identification of csk tyrosine phosphorylation sites and a tyrosine residue important for kinase domain structure." Joukov V., Vihinen M., Vainikka S., Sowadski J.M., Alitalo K., Bergman M. Biochem. J. 322:927-935(1997) [PubMed: 9148770] [Abstract] Cited for: PHOSPHORYLATION AT TYR-184 AND TYR-304, MUTAGENESIS OF TYR-184 AND TYR-304.
[9]	"Phosphorylation of Hic-5 at tyrosine 60 by CAKbeta and Fyn." Ishino M., Aoto H., Sasaski H., Suzuki R., Sasaki T. FEBS Lett. 474:179-183(2000) [PubMed: 10838081] [Abstract] Cited for: INTERACTION WITH TGFB1I1.
[10]	"Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation." Brdicka T., Pavlistova D., Bruyns E., Leo A., Korinek V., Angelisova P., Scherer J., Shevchenko A., Shevchenko A., Hilgert I., Cerny J., Drbal K., Kuramitsu Y., Horejsi V., Schraven B. J. Exp. Med. 191:1591-1604(2000) [PubMed: 10790433] [Abstract] Cited for: INTERACTION WITH PAG1.
[11]	"Structural and functional dissection of the cytoplasmic domain of the transmembrane adaptor protein SIT (SHP2-interacting transmembrane adaptor protein)." Pfrepper K.-I., Marie-Cardine A., Simeoni L., Kuramitsu Y., Leo A., Spicka J., Hilgert I., Scherer J., Schraven B. Eur. J. Immunol. 31:1825-1836(2001) [PubMed: 11433379] [Abstract] Cited for: INTERACTION WITH SIT1.
[12]	"LIME: a new membrane raft-associated adaptor protein involved in CD4 and CD8 coreceptor signaling." Brdickova N., Brdicka T., Angelisova P., Horvath O., Spicka J., Hilgert I., Paces J., Simeoni L., Kliche S., Merten C., Schraven B., Horejsi V. J. Exp. Med. 198:1453-1462(2003) [PubMed: 14610046] [Abstract] Cited for: INTERACTION WITH LIME1.
[13]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-184, MASS SPECTROMETRY.
[14]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[15]	"The crystal structure of human CskSH3: structural diversity near the RT-Src and n-Src loop." Borchert T.V., Mathieu M., Zeelen J.P., Courtneidge S.A., Wierenga R.K. FEBS Lett. 341:79-85(1994) [PubMed: 7511113] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-71.
[16]	"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: VARIANT [LARGE SCALE ANALYSIS] LEU-45.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

X60114 mRNA. Translation: CAA42713.1.
X59932 mRNA. Translation: CAA42556.1.
X74765 Genomic DNA. Translation: CAB58562.1.
CR541960 mRNA. Translation: CAG46758.1.
DQ075211 Genomic DNA. Translation: AAY57329.1.
BC104847 mRNA. Translation: AAI04848.1.
BC104875 mRNA. Translation: AAI04876.1.
BC106073 mRNA. Translation: AAI06074.1.

IPI

IPI00013212.

PIR

JH0559.

RefSeq

NP_001120662.1.
NP_004374.1.

UniGene

Hs.77793

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BYG	X-ray	2.40	A	177-450	[»]
1CSK	X-ray	2.50	A/B/C/D	1-71	[»]
3D7T	X-ray	2.90	A	188-450	[»]
3D7U	X-ray	4.11	A/C	188-450	[»]

SMR

P41240. Positions 4-450.

ModBase

Search...

Protein-protein interaction databases

IntAct

P41240. 19 interactions.

PTM databases

PhosphoSite

P41240.

2-D gel databases

OGP

P41240.

Proteomic databases

PRIDE

P41240.

Genome annotation databases

Ensembl

ENSG00000103653. Homo sapiens. [Contig view]

GeneID

1445.

KEGG

hsa:1445.

Organism-specific databases

GeneCards

GC15P072861.

H-InvDB

HIX0026799.

HGNC

HGNC:2444. CSK.

HPA

CAB011203.

MIM

124095. gene.

PharmGKB

PA26946.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P41240.

HOVERGEN

P41240.

OMA

P41240. QDLPFCK.

Enzyme and pathway databases

BRENDA

2.7.10.2. 247.

Pathway_Interaction_DB

bcr_5pathway. BCR signaling pathway.
pdgfrbpathway. PDGFR-beta signaling pathway.
ptp1bpathway. Signaling events mediated by PTP1B.
tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.

Reactome

REACT_6900. Signaling in Immune system.
REACT_9417. Signaling by EGFR.

Gene expression databases

ArrayExpress

P41240.

Bgee

P41240.

CleanEx

HS_CSK.

GermOnline

ENSG00000103653. Homo sapiens.

Family and domain databases

InterPro

IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR000980. SH2.
IPR001452. SH3_domain.
IPR001245. Tyr_pkinase.
IPR008266. Tyr_pkinase_AS.
IPR015778. Tyrosine_Protein_Kinase_Csk.
[Graphical view]

Gene3D

G3DSA:3.30.505.10. SH2. 1 hit.

PANTHER

PTHR23256:SF264. Csk_ProtTyrKin. 1 hit.

Pfam

PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]

PRINTS

PR00401. SH2DOMAIN.
PR00109. TYRKINASE.

ProDom

PD000001. Prot_kinase. 1 hit.
PD000093. SH2. 1 hit.
PD000066. SH3. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

5937.

SOURCE

Search...

Entry information

Entry name

CSK_HUMAN

Accession

Primary (citable) accession number: P41240
Secondary accession number(s): Q2M3N2, Q6FGZ6

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	February 1, 1995
Last modified:	June 16, 2009
This is version 111 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)