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Protein

Tyrosine-protein kinase CSK

Gene

CSK

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK.2 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.3 Publications

Cofactori

Mg2+1 Publication, Mn2+1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei222ATPPROSITE-ProRule annotation1
Active sitei314Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi201 – 209ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • identical protein binding Source: IntAct
  • kinase activity Source: Reactome
  • metal ion binding Source: UniProtKB-KW
  • non-membrane spanning protein tyrosine kinase activity Source: GO_Central
  • protein C-terminus binding Source: ProtInc
  • protein kinase A catalytic subunit binding Source: UniProtKB
  • protein tyrosine kinase activity Source: Reactome
  • receptor binding Source: GO_Central

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Adaptive immunity, Immunity

Keywords - Ligandi

ATP-binding, Magnesium, Manganese, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS02526-MONOMER.
BRENDAi2.7.10.2. 2681.
ReactomeiR-HSA-180292. GAB1 signalosome.
R-HSA-202427. Phosphorylation of CD3 and TCR zeta chains.
R-HSA-354192. Integrin alphaIIb beta3 signaling.
R-HSA-389948. PD-1 signaling.
R-HSA-5674135. MAP2K and MAPK activation.
R-HSA-6802946. Signaling by moderate kinase activity BRAF mutants.
R-HSA-6802948. Signaling by high-kinase activity BRAF mutants.
R-HSA-6802949. Signaling by RAS mutants.
R-HSA-6802952. Signaling by BRAF and RAF fusions.
R-HSA-6802955. Paradoxical activation of RAF signaling by kinase inactive BRAF.
SignaLinkiP41240.
SIGNORiP41240.

Names & Taxonomyi

Protein namesi
Recommended name:
Tyrosine-protein kinase CSK (EC:2.7.10.23 Publications)
Alternative name(s):
C-Src kinase
Protein-tyrosine kinase CYL
Gene namesi
Name:CSK
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 15

Organism-specific databases

HGNCiHGNC:2444. CSK.

Subcellular locationi

  • Cytoplasm By similarity
  • Cell membrane By similarity

  • Note: Mainly cytoplasmic, also present in lipid rafts.By similarity

GO - Cellular componenti

  • cell-cell junction Source: Ensembl
  • cytoplasm Source: HGNC
  • cytosol Source: Reactome
  • extracellular exosome Source: UniProtKB
  • extrinsic component of cytoplasmic side of plasma membrane Source: GO_Central
  • membrane raft Source: Ensembl
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi184Y → F: Abolishes phosphorylation. 1 Publication1
Mutagenesisi304Y → F: Decreases activity by two-thirds and alters conformation. 1 Publication1
Mutagenesisi364S → A: Strong decrease of phosphorylation by PRKACA (catalytic subunit of PKA). 1 Publication1

Organism-specific databases

DisGeNETi1445.
OpenTargetsiENSG00000103653.
PharmGKBiPA26946.

Chemistry databases

ChEMBLiCHEMBL2634.
GuidetoPHARMACOLOGYi1994.

Polymorphism and mutation databases

BioMutaiCSK.
DMDMi729887.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000880702 – 450Tyrosine-protein kinase CSKAdd BLAST449

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineCombined sources1
Modified residuei184Phosphotyrosine1 Publication1
Modified residuei304Phosphotyrosine1 Publication1
Modified residuei364Phosphoserine; by PKA1 Publication1
Modified residuei416Phosphotyrosine; by autocatalysis1 Publication1

Post-translational modificationi

Phosphorylated at Ser-364 by PKA, leading to increased activity. Autophosphorylated.2 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP41240.
MaxQBiP41240.
PaxDbiP41240.
PeptideAtlasiP41240.
PRIDEiP41240.

2D gel databases

OGPiP41240.

PTM databases

iPTMnetiP41240.
PhosphoSitePlusiP41240.

Expressioni

Tissue specificityi

Expressed in lung and macrophages.1 Publication

Gene expression databases

BgeeiENSG00000103653.
CleanExiHS_CSK.
ExpressionAtlasiP41240. baseline and differential.
GenevisibleiP41240. HS.

Organism-specific databases

HPAiCAB011203.
HPA026488.
HPA028425.

Interactioni

Subunit structurei

Homodimer (via SH3-domain) (PubMed:19888460). Interacts with PTPN22 (PubMed:15208781). Interacts with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1; these interactions serve to recruit CSK to the membrane where it can phosphorylate and inhibit Src-family kinases (PubMed:11433379, PubMed:10790433, PubMed:14610046, PubMed:10838081). Interacts with SRCIN1 (PubMed:17525734). Interacts with RHOH (PubMed:20851766). Interacts (via SH2 domain) with SCIMP (PubMed:21930792).8 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself7EBI-1380630,EBI-1380630
IGF1RP080695EBI-1380630,EBI-475981
PAG1Q9NWQ83EBI-1380630,EBI-2828115
PTPRCP085753EBI-1380630,EBI-1341
PXNP490232EBI-1380630,EBI-702209
SRCP005236EBI-1380630,EBI-848039From a different organism.

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • protein C-terminus binding Source: ProtInc
  • protein kinase A catalytic subunit binding Source: UniProtKB
  • receptor binding Source: GO_Central

Protein-protein interaction databases

BioGridi107832. 54 interactors.
IntActiP41240. 38 interactors.
MINTiMINT-85878.
STRINGi9606.ENSP00000220003.

Chemistry databases

BindingDBiP41240.

Structurei

Secondary structure

1450
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi12 – 18Combined sources7
Beta strandi35 – 41Combined sources7
Beta strandi47 – 51Combined sources5
Beta strandi57 – 61Combined sources5
Beta strandi64 – 66Combined sources3
Helixi77 – 79Combined sources3
Beta strandi83 – 86Combined sources4
Helixi89 – 95Combined sources7
Beta strandi103 – 108Combined sources6
Beta strandi116 – 122Combined sources7
Beta strandi125 – 130Combined sources6
Beta strandi132 – 134Combined sources3
Beta strandi137 – 144Combined sources8
Beta strandi146 – 148Combined sources3
Helixi149 – 158Combined sources10
Beta strandi163 – 165Combined sources3
Helixi192 – 194Combined sources3
Beta strandi195 – 203Combined sources9
Beta strandi208 – 214Combined sources7
Beta strandi217 – 223Combined sources7
Helixi231 – 235Combined sources5
Helixi237 – 240Combined sources4
Beta strandi251 – 255Combined sources5
Beta strandi263 – 266Combined sources4
Helixi274 – 285Combined sources12
Helixi288 – 307Combined sources20
Helixi317 – 319Combined sources3
Beta strandi320 – 322Combined sources3
Beta strandi328 – 330Combined sources3
Turni350 – 352Combined sources3
Helixi355 – 360Combined sources6
Helixi365 – 380Combined sources16
Helixi392 – 394Combined sources3
Helixi395 – 399Combined sources5
Turni400 – 402Combined sources3
Helixi413 – 422Combined sources10
Helixi427 – 429Combined sources3
Helixi433 – 446Combined sources14

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1BYGX-ray2.40A173-450[»]
1CSKX-ray2.50A/B/C/D1-71[»]
3D7TX-ray2.90A188-450[»]
3D7UX-ray4.11A/C188-450[»]
3EACX-ray1.37A73-178[»]
3EAZX-ray1.31A73-178[»]
ProteinModelPortaliP41240.
SMRiP41240.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP41240.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini9 – 70SH3PROSITE-ProRule annotationAdd BLAST62
Domaini82 – 171SH2PROSITE-ProRule annotationAdd BLAST90
Domaini195 – 449Protein kinasePROSITE-ProRule annotationAdd BLAST255

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni9 – 70Interaction with PTPN22By similarityAdd BLAST62

Domaini

The architecture of this protein is similar to that of Src-family kinases (SFKs) with one N-terminal SH3 domain, one SH2 domain, and a C-terminal kinase domain.

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. CSK subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 SH2 domain.PROSITE-ProRule annotation
Contains 1 SH3 domain.PROSITE-ProRule annotation

Keywords - Domaini

SH2 domain, SH3 domain

Phylogenomic databases

eggNOGiKOG0197. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000119011.
HOGENOMiHOG000233858.
HOVERGENiHBG008761.
InParanoidiP41240.
KOiK05728.
OMAiTRDPNWY.
OrthoDBiEOG091G05PB.
PhylomeDBiP41240.
TreeFamiTF351634.

Family and domain databases

Gene3Di3.30.505.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR000980. SH2.
IPR001452. SH3_domain.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]
PRINTSiPR00401. SH2DOMAIN.
PR00109. TYRKINASE.
SMARTiSM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P41240-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSAIQAAWPS GTECIAKYNF HGTAEQDLPF CKGDVLTIVA VTKDPNWYKA
60 70 80 90 100
KNKVGREGII PANYVQKREG VKAGTKLSLM PWFHGKITRE QAERLLYPPE
110 120 130 140 150
TGLFLVREST NYPGDYTLCV SCDGKVEHYR IMYHASKLSI DEEVYFENLM
160 170 180 190 200
QLVEHYTSDA DGLCTRLIKP KVMEGTVAAQ DEFYRSGWAL NMKELKLLQT
210 220 230 240 250
IGKGEFGDVM LGDYRGNKVA VKCIKNDATA QAFLAEASVM TQLRHSNLVQ
260 270 280 290 300
LLGVIVEEKG GLYIVTEYMA KGSLVDYLRS RGRSVLGGDC LLKFSLDVCE
310 320 330 340 350
AMEYLEGNNF VHRDLAARNV LVSEDNVAKV SDFGLTKEAS STQDTGKLPV
360 370 380 390 400
KWTAPEALRE KKFSTKSDVW SFGILLWEIY SFGRVPYPRI PLKDVVPRVE
410 420 430 440 450
KGYKMDAPDG CPPAVYEVMK NCWHLDAAMR PSFLQLREQL EHIKTHELHL
Length:450
Mass (Da):50,704
Last modified:February 1, 1995 - v1
Checksum:i431023A88C54E00C
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04167845P → L.1 Publication1
Natural variantiVAR_025203287G → D.1 PublicationCorresponds to variant rs34866753dbSNPEnsembl.1
Natural variantiVAR_025204398R → Q.1 PublicationCorresponds to variant rs34616395dbSNPEnsembl.1
Natural variantiVAR_025205442H → R.1 PublicationCorresponds to variant rs35556162dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS10269.1.
PIRiJH0559.
RefSeqiNP_001120662.1. NM_001127190.1.
NP_004374.1. NM_004383.2.
XP_005254222.1. XM_005254165.4.
XP_016877414.1. XM_017021925.1.
UniGeneiHs.77793.

Genome annotation databases

EnsembliENST00000220003; ENSP00000220003; ENSG00000103653.
ENST00000439220; ENSP00000414764; ENSG00000103653.
ENST00000567571; ENSP00000454906; ENSG00000103653.
GeneIDi1445.
KEGGihsa:1445.
UCSCiuc002ays.3. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Web resourcesi

NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS10269.1.
PIRiJH0559.
RefSeqiNP_001120662.1. NM_001127190.1.
NP_004374.1. NM_004383.2.
XP_005254222.1. XM_005254165.4.
XP_016877414.1. XM_017021925.1.
UniGeneiHs.77793.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1BYGX-ray2.40A173-450[»]
1CSKX-ray2.50A/B/C/D1-71[»]
3D7TX-ray2.90A188-450[»]
3D7UX-ray4.11A/C188-450[»]
3EACX-ray1.37A73-178[»]
3EAZX-ray1.31A73-178[»]
ProteinModelPortaliP41240.
SMRiP41240.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107832. 54 interactors.
IntActiP41240. 38 interactors.
MINTiMINT-85878.
STRINGi9606.ENSP00000220003.

Chemistry databases

BindingDBiP41240.
ChEMBLiCHEMBL2634.
GuidetoPHARMACOLOGYi1994.

PTM databases

iPTMnetiP41240.
PhosphoSitePlusiP41240.

Polymorphism and mutation databases

BioMutaiCSK.
DMDMi729887.

2D gel databases

OGPiP41240.

Proteomic databases

EPDiP41240.
MaxQBiP41240.
PaxDbiP41240.
PeptideAtlasiP41240.
PRIDEiP41240.

Protocols and materials databases

DNASUi1445.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000220003; ENSP00000220003; ENSG00000103653.
ENST00000439220; ENSP00000414764; ENSG00000103653.
ENST00000567571; ENSP00000454906; ENSG00000103653.
GeneIDi1445.
KEGGihsa:1445.
UCSCiuc002ays.3. human.

Organism-specific databases

CTDi1445.
DisGeNETi1445.
GeneCardsiCSK.
HGNCiHGNC:2444. CSK.
HPAiCAB011203.
HPA026488.
HPA028425.
MIMi124095. gene.
neXtProtiNX_P41240.
OpenTargetsiENSG00000103653.
PharmGKBiPA26946.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0197. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000119011.
HOGENOMiHOG000233858.
HOVERGENiHBG008761.
InParanoidiP41240.
KOiK05728.
OMAiTRDPNWY.
OrthoDBiEOG091G05PB.
PhylomeDBiP41240.
TreeFamiTF351634.

Enzyme and pathway databases

BioCyciZFISH:HS02526-MONOMER.
BRENDAi2.7.10.2. 2681.
ReactomeiR-HSA-180292. GAB1 signalosome.
R-HSA-202427. Phosphorylation of CD3 and TCR zeta chains.
R-HSA-354192. Integrin alphaIIb beta3 signaling.
R-HSA-389948. PD-1 signaling.
R-HSA-5674135. MAP2K and MAPK activation.
R-HSA-6802946. Signaling by moderate kinase activity BRAF mutants.
R-HSA-6802948. Signaling by high-kinase activity BRAF mutants.
R-HSA-6802949. Signaling by RAS mutants.
R-HSA-6802952. Signaling by BRAF and RAF fusions.
R-HSA-6802955. Paradoxical activation of RAF signaling by kinase inactive BRAF.
SignaLinkiP41240.
SIGNORiP41240.

Miscellaneous databases

EvolutionaryTraceiP41240.
GeneWikiiC-src_tyrosine_kinase.
GenomeRNAii1445.
PROiP41240.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000103653.
CleanExiHS_CSK.
ExpressionAtlasiP41240. baseline and differential.
GenevisibleiP41240. HS.

Family and domain databases

Gene3Di3.30.505.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR000980. SH2.
IPR001452. SH3_domain.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]
PRINTSiPR00401. SH2DOMAIN.
PR00109. TYRKINASE.
SMARTiSM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. 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]
ProtoNetiSearch...

Entry informationi

Entry nameiCSK_HUMAN
AccessioniPrimary (citable) accession number: P41240
Secondary accession number(s): Q2M3N2, Q6FGZ6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: November 30, 2016
This is version 193 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 15
    Human chromosome 15: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.