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Protein

Tyrosine-protein kinase CSK

Gene

CSK

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

GO - Biological processi

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
Biological processAdaptive immunity, Immunity
LigandATP-binding, Magnesium, Manganese, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

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

EuPathDBiHostDB:ENSG00000103653.16
HGNCiHGNC:2444 CSK
MIMi124095 gene
neXtProtiNX_P41240

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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
DrugBankiDB02010 Staurosporine
DB05075 TG100801
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
ProteomicsDBi55450

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

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • proline-rich region binding Source: Ensembl
  • protein C-terminus binding Source: ProtInc
  • protein kinase A catalytic subunit binding Source: UniProtKB
  • protein phosphatase binding Source: Ensembl
  • signaling receptor binding Source: GO_Central

Protein-protein interaction databases

BioGridi107832, 58 interactors
ELMiP41240
IntActiP41240, 39 interactors
MINTiP41240
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

Keywords - Domaini

SH2 domain, SH3 domain

Phylogenomic databases

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

Family and domain databases

CDDicd09937 SH2_csk_like, 1 hit
Gene3Di3.30.505.10, 1 hit
InterProiView protein in InterPro
IPR035026 CSK
IPR035027 Csk-like_SH2
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR000980 SH2
IPR036860 SH2_dom_sf
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
PANTHERiPTHR24418:SF307 PTHR24418:SF307, 1 hit
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
PF00017 SH2, 1 hit
PF00018 SH3_1, 1 hit
PRINTSiPR00401 SH2DOMAIN
PR00109 TYRKINASE
SMARTiView protein in SMART
SM00252 SH2, 1 hit
SM00326 SH3, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF50044 SSF50044, 1 hit
SSF55550 SSF55550, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in 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

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 → L1 Publication1
Natural variantiVAR_025203287G → D1 PublicationCorresponds to variant dbSNP:rs34866753Ensembl.1
Natural variantiVAR_025204398R → Q1 PublicationCorresponds to variant dbSNP:rs34616395Ensembl.1
Natural variantiVAR_025205442H → R1 PublicationCorresponds to variant dbSNP:rs35556162Ensembl.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

Similar proteinsi

Entry informationi

Entry nameiCSK_HUMAN
AccessioniPrimary (citable) accession number: P41240
Secondary accession number(s): Q2M3N2, Q6FGZ6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: June 20, 2018
This is version 206 of the entry and version 1 of the sequence. See 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

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