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UniProtKB - P46108 (CRK_HUMAN)

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Protein

Adapter molecule crk

Gene

CRK

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

Functioni

Isoform Crk-II: Regulates cell adhesion, spreading and migration. Mediates attachment-induced MAPK8 activation, membrane ruffling and cell motility in a Rac-dependent manner. Involved in phagocytosis of apoptotic cells and cell motility via its interaction with DOCK1 and DOCK4. May regulate the EFNA5-EPHA3 signaling.4 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei237Proline switchBy similarity1

GO - Molecular functioni

  • cytoskeletal protein binding Source: Ensembl
  • ephrin receptor binding Source: UniProtKB
  • insulin-like growth factor receptor binding Source: Ensembl
  • phosphotyrosine binding Source: CAFA
  • protein phosphorylated amino acid binding Source: CAFA
  • protein self-association Source: CAFA
  • protein tyrosine kinase binding Source: CAFA
  • scaffold protein binding Source: Ensembl
  • SH2 domain binding Source: UniProtKB
  • SH3/SH2 adaptor activity Source: CAFA
  • SH3 domain binding Source: CAFA
Complete GO annotation...

GO - Biological processi

Complete GO annotation...

Enzyme and pathway databases

ReactomeiR-HSA-170984. ARMS-mediated activation.
R-HSA-186763. Downstream signal transduction.
R-HSA-2029482. Regulation of actin dynamics for phagocytic cup formation.
R-HSA-372708. p130Cas linkage to MAPK signaling for integrins.
R-HSA-4420097. VEGFA-VEGFR2 Pathway.
R-HSA-8849471. PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.
R-HSA-8875555. MET activates RAP1 and RAC1.
R-HSA-8875656. MET receptor recycling.
R-HSA-912631. Regulation of signaling by CBL.
SignaLinkiP46108.
SIGNORiP46108.

Names & Taxonomyi

Protein namesi
Recommended name:
Adapter molecule crk
Alternative name(s):
Proto-oncogene c-Crk
p38
Gene namesi
Name:CRK
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

HGNCiHGNC:2362. CRK.

Subcellular locationi

  • Cytoplasm By similarity
  • Cell membrane By similarity

    • Note: Translocated to the plasma membrane upon cell adhesion.By similarity

GO - Cellular componenti

  • actin cytoskeleton Source: Ensembl
  • cytoplasm Source: UniProtKB
  • cytosol Source: Reactome
  • extracellular exosome Source: UniProtKB
  • membrane raft Source: Ensembl
  • nucleus Source: ProtInc
  • plasma membrane Source: UniProtKB-SubCell
  • protein complex Source: CAFA
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi150D → K: Abolishes interaction with DOCK1. 1 Publication1
Mutagenesisi169W → L: Abolishes interaction with DOCK5. 1 Publication1

Keywords - Diseasei

Proto-oncogene

Organism-specific databases

DisGeNETi1398.
OpenTargetsiENSG00000167193.
PharmGKBiPA26880.

Chemistry databases

ChEMBLiCHEMBL5005.

Polymorphism and mutation databases

BioMutaiCRK.
DMDMi158939322.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000793512 – 304Adapter molecule crkAdd BLAST303

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1
Modified residuei40PhosphoserineCombined sources1
Modified residuei41PhosphoserineCombined sources1
Modified residuei74PhosphoserineCombined sources1
Modified residuei83PhosphoserineCombined sources1
Modified residuei108PhosphotyrosineCombined sources1
Modified residuei125PhosphoserineCombined sources1
Modified residuei221Phosphotyrosine; by ABL11 Publication1
Modified residuei239PhosphotyrosineCombined sources1
Isoform Crk-I (identifier: P46108-2)
Modified residuei194PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylation of Crk-II (40 kDa) gives rise to a 42 kDa form. Isoform Crk-II is phosphorylated by KIT.
Phosphorylated on Tyr-221 upon cell adhesion. Results in the negative regulation of the association with SH2- and SH3-binding partners, possibly by the formation of an intramolecular interaction of phosphorylated Tyr-221 with the SH2 domain. This leads finally to the down-regulation of the Crk signaling pathway.1 Publication
Proline isomerization at Pro-237 by PPIA acts as a switch between two conformations: an autoinhibitory conformation in the cis form, where the tandem SH3 domains interact intramolecularly, and an activated conformation in the trans form.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP46108.
MaxQBiP46108.
PaxDbiP46108.
PeptideAtlasiP46108.
PRIDEiP46108.
TopDownProteomicsiP46108-1. [P46108-1]
P46108-2. [P46108-2]

2D gel databases

REPRODUCTION-2DPAGEiIPI00399054.
SWISS-2DPAGEiP46108.

PTM databases

iPTMnetiP46108.
PhosphoSitePlusiP46108.

Expressioni

Gene expression databases

BgeeiENSG00000167193.
CleanExiHS_CRK.
ExpressionAtlasiP46108. baseline and differential.
GenevisibleiP46108. HS.

Organism-specific databases

HPAiCAB010485.
HPA068087.

Interactioni

Subunit structurei

Interacts with ABL1, C3G, DOCK3, DOCK5, MAP4K1, MAPK8 and SOS via its first SH3 domain. Interacts (via SH2 domain) with BCAR1, CBL, CBLB, PXN, IRS4 and GAB1 upon stimulus-induced tyrosine phosphorylation. Interacts (via SH2 domain) with several tyrosine-phosphorylated growth factor receptors such as EGFR and INSR. Interacts with FLT1 (tyrosine-phosphorylated). Interacts with DOCK1 and DOCK4. Interacts with SHB. Interacts with PEAK1. Interacts with FASLG. Isoform Crk-II interacts with KIT. Interacts with EPHA3; upon activation of EPHA3 by the ligand EFNA5 and EPHA3 tyrosine kinase activity-dependent. Interacts with EPHA3 (phosphorylated); mediates EFNA5-EPHA3 signaling through RHOA GTPase activation. Interacts with FLT4 (tyrosine-phosphorylated). Isoform Crk-II (via SH2 domain) interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and p130cas/BCAR1. Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1. Interacts with CBLC. Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases.16 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • cytoskeletal protein binding Source: Ensembl
  • ephrin receptor binding Source: UniProtKB
  • insulin-like growth factor receptor binding Source: Ensembl
  • phosphotyrosine binding Source: CAFA
  • protein phosphorylated amino acid binding Source: CAFA
  • protein self-association Source: CAFA
  • protein tyrosine kinase binding Source: CAFA
  • scaffold protein binding Source: Ensembl
  • SH2 domain binding Source: UniProtKB
  • SH3/SH2 adaptor activity Source: CAFA
  • SH3 domain binding Source: CAFA
Complete GO annotation...

Protein-protein interaction databases

BioGridi107788. 254 interactors.
DIPiDIP-199N.
IntActiP46108. 273 interactors.
MINTiMINT-1208745.
STRINGi9606.ENSP00000300574.

Structurei

Secondary structure

1304
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi7 – 13Combined sources7
Beta strandi14 – 16Combined sources3
Helixi20 – 27Combined sources8
Beta strandi30 – 33Combined sources4
Beta strandi34 – 39Combined sources6
Beta strandi41 – 43Combined sources3
Beta strandi46 – 52Combined sources7
Beta strandi54 – 56Combined sources3
Beta strandi57 – 63Combined sources7
Beta strandi66 – 69Combined sources4
Beta strandi70 – 77Combined sources8
Turni78 – 80Combined sources3
Beta strandi87 – 89Combined sources3
Beta strandi92 – 96Combined sources5
Helixi97 – 106Combined sources10
Beta strandi109 – 112Combined sources4
Beta strandi116 – 118Combined sources3
Beta strandi120 – 123Combined sources4
Helixi126 – 128Combined sources3
Beta strandi135 – 138Combined sources4
Beta strandi146 – 150Combined sources5
Beta strandi158 – 166Combined sources9
Beta strandi167 – 173Combined sources7
Beta strandi179 – 183Combined sources5
Helixi184 – 186Combined sources3
Beta strandi187 – 189Combined sources3
Beta strandi208 – 210Combined sources3
Beta strandi224 – 227Combined sources4
Beta strandi229 – 231Combined sources3
Beta strandi239 – 242Combined sources4
Beta strandi253 – 255Combined sources3
Beta strandi260 – 269Combined sources10
Beta strandi273 – 279Combined sources7
Beta strandi282 – 287Combined sources6
Helixi288 – 290Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1JU5NMR-A12-120[»]
2DVJNMR-A1-228[»]
2EYVNMR-A6-124[»]
2EYWNMR-A125-198[»]
2EYXNMR-A232-298[»]
2EYYNMR-A1-204[»]
2EYZNMR-A1-304[»]
2MS4NMR-B216-224[»]
DisProtiDP00748.
ProteinModelPortaliP46108.
SMRiP46108.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP46108.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini13 – 118SH2PROSITE-ProRule annotationAdd BLAST106
Domaini132 – 192SH3 1PROSITE-ProRule annotationAdd BLAST61
Domaini237 – 296SH3 2PROSITE-ProRule annotationAdd BLAST60

Domaini

The C-terminal SH3 domain function as a negative modulator for transformation and the N-terminal SH3 domain appears to function as a positive regulator for transformation.By similarity
The SH2 domain mediates interaction with tyrosine phosphorylated proteins. Mediates interaction with SHB.

Sequence similaritiesi

Belongs to the CRK family.Curated

Keywords - Domaini

Repeat, SH2 domain, SH3 domain

Phylogenomic databases

eggNOGiKOG4792. Eukaryota.
ENOG4110574. LUCA.
GeneTreeiENSGT00820000127055.
HOGENOMiHOG000236288.
HOVERGENiHBG105616.
InParanoidiP46108.
KOiK04438.
OMAiGSWYWGR.
OrthoDBiEOG091G0JPQ.
PhylomeDBiP46108.
TreeFamiTF321436.

Family and domain databases

Gene3Di3.30.505.10. 1 hit.
InterProiView protein in InterPro
IPR000980. SH2.
IPR011511. SH3_2.
IPR001452. SH3_domain.
PfamiView protein in Pfam
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
PF07653. SH3_2. 1 hit.
PRINTSiPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
SMARTiView protein in SMART
SM00252. SH2. 1 hit.
SM00326. SH3. 2 hits.
SUPFAMiSSF50044. SSF50044. 3 hits.
SSF55550. SSF55550. 2 hits.
PROSITEiView protein in PROSITE
PS50001. SH2. 1 hit.
PS50002. SH3. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform Crk-II (identifier: P46108-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MAGNFDSEER SSWYWGRLSR QEAVALLQGQ RHGVFLVRDS STSPGDYVLS 
        60         70         80         90        100
VSENSRVSHY IINSSGPRPP VPPSPAQPPP GVSPSRLRIG DQEFDSLPAL 
       110        120        130        140        150
LEFYKIHYLD TTTLIEPVSR SRQGSGVILR QEEAEYVRAL FDFNGNDEED 
       160        170        180        190        200
LPFKKGDILR IRDKPEEQWW NAEDSEGKRG MIPVPYVEKY RPASASVSAL 
       210        220        230        240        250
IGGNQEGSHP QPLGGPEPGP YAQPSVNTPL PNLQNGPIYA RVIQKRVPNA 
       260        270        280        290        300
YDKTALALEV GELVKVTKIN VSGQWEGECN GKRGHFPFTH VRLLDQQNPD 

EDFS
Length:304
Mass (Da):33,831
Last modified:July 24, 2007 - v2
Checksum:i4CFBFB65BFC2E265
GO
Isoform Crk-I (identifier: P46108-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     204-204: N → R
     205-304: Missing.

Show »
Length:204
Mass (Da):22,906
Checksum:iB4C5BF23887B6B80
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti109L → W in BAA01505 (PubMed:1630456).Curated1
Sequence conflicti109L → W in AAB28213 (PubMed:8378094).Curated1
Sequence conflicti215G → P in BAA01505 (PubMed:1630456).Curated1
Sequence conflicti215G → P in AAB28213 (PubMed:8378094).Curated1
Sequence conflicti278E → G in BAA01505 (PubMed:1630456).Curated1
Sequence conflicti278E → G in AAB28213 (PubMed:8378094).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_041153204N → R in isoform Crk-I. 2 Publications1
Alternative sequenceiVSP_041154205 – 304Missing in isoform Crk-I. 2 PublicationsAdd BLAST100

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D10656 mRNA. Translation: BAA01505.1.
S65701 Genomic DNA. Translation: AAB28213.1.
BT007277 mRNA. Translation: AAP35941.1.
EU332838 Genomic DNA. Translation: ABY87527.1.
AK291060 mRNA. Translation: BAF83749.1.
AC032044 Genomic DNA. No translation available.
AC100748 Genomic DNA. No translation available.
CH471108 Genomic DNA. Translation: EAW90621.1.
CH471108 Genomic DNA. Translation: EAW90624.1.
CH471108 Genomic DNA. Translation: EAW90625.1.
BC001718 mRNA. Translation: AAH01718.1.
BC008506 mRNA. Translation: AAH08506.1.
BC009837 mRNA. Translation: AAH09837.1.
CCDSiCCDS11002.1. [P46108-1]
CCDS45561.1. [P46108-2]
PIRiA45022.
RefSeqiNP_005197.3. NM_005206.4. [P46108-2]
NP_058431.2. NM_016823.3. [P46108-1]
UniGeneiHs.461896.

Genome annotation databases

EnsembliENST00000300574; ENSP00000300574; ENSG00000167193. [P46108-1]
ENST00000398970; ENSP00000381942; ENSG00000167193. [P46108-2]
GeneIDi1398.
KEGGihsa:1398.
UCSCiuc002fsl.4. human. [P46108-1]

Keywords - Coding sequence diversityi

Alternative splicing

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.

Entry informationi

Entry nameiCRK_HUMAN
AccessioniPrimary (citable) accession number: P46108
Secondary accession number(s): A8MWE8
, B0LPE8, D3DTH6, Q96GA9, Q96HJ0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: July 24, 2007
Last modified: July 5, 2017
This is version 186 of the entry and version 2 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 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families