O43639 (NCK2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cytoplasmic protein NCK2

Alternative name(s):
Growth factor receptor-bound protein 4
NCK adaptor protein 2
Short name=Nck-2
SH2/SH3 adaptor protein NCK-beta

Gene names

Name:	NCK2
Synonyms:	GRB4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	380 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Adapter protein which associates with tyrosine-phosphorylated growth factor receptors or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling. Ref.5 Ref.10
Subunit structure	Interacts with DOCK1, LIMS1 and TGFB1I1. Part of a complex containing PPP1R15B, PP1 and NCK2. Interacts with FASLG By similarity. Interacts with AXL. Interacts with PAK1, PKN2 and SOS1. Interacts (via SH2 domain) with EGFR. Interacts (via SH2 domain) with DDR1. Ref.2 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.12
Subcellular location	Cytoplasm. Endoplasmic reticulum Ref.10.
Tissue specificity	Ubiquitous.
Post-translational modification	Phosphorylated. Ref.5
Sequence similarities	Contains 1 SH2 domain. Contains 3 SH3 domains.

Ontologies

Keywords
Biological process	Translation regulation
Cellular component	Cytoplasm Endoplasmic reticulum
Domain	Repeat SH2 domain SH3 domain
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	T cell activation Non-traceable author statement PubMed 12110186. Source: UniProtKB actin filament organization Inferred from electronic annotation. Source: Compara axon guidance Traceable author statement. Source: Reactome cell migration Inferred from electronic annotation. Source: Compara epidermal growth factor receptor signaling pathway Traceable author statement Ref.1. Source: ProtInc lamellipodium assembly Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Traceable author statement Ref.1. Source: ProtInc positive regulation of T cell proliferation Inferred from mutant phenotype PubMed 12110186. Source: UniProtKB positive regulation of actin filament polymerization Inferred from mutant phenotype PubMed 12110186. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay Ref.5. Source: UniProtKB regulation of epidermal growth factor-activated receptor activity Traceable author statement Ref.1. Source: ProtInc regulation of translation Inferred from electronic annotation. Source: UniProtKB-KW signal complex assembly Non-traceable author statement PubMed 12110186. Source: UniProtKB
Cellular_component	cytosol Traceable author statement. Source: Reactome endoplasmic reticulum Inferred from electronic annotation. Source: UniProtKB-SubCell vesicle membrane Inferred from electronic annotation. Source: Compara
Molecular_function	cytoskeletal adaptor activity Non-traceable author statement PubMed 12110186. Source: UniProtKB receptor signaling complex scaffold activity Non-traceable author statement PubMed 12110186. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
RHOU	Q7L0Q8	4	EBI-713635,EBI-1638043

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 380

380

Cytoplasmic protein NCK2

PRO_0000096767

Regions

Domain

2 – 61

60

SH3 1

Domain

111 – 170

60

SH3 2

Domain

195 – 257

63

SH3 3

Domain

285 – 380

96

SH2

Amino acid modifications

Modified residue

90

1

Phosphoserine Ref.13

Modified residue

110

1

Phosphotyrosine Ref.11

Modified residue

342

1

Phosphotyrosine By similarity

Experimental info

Mutagenesis

148

1

W → K: Abolishes interaction with DOCK1. Ref.7

Mutagenesis

234

1

W → K: Abolishes interaction with DOCK1. Ref.7

Sequence conflict

25

1

K → KV in AAC04831. Ref.1

Sequence conflict

100

1

P → A in AAC80284. Ref.2

Sequence conflict

296

1

E → Q in AAC04831. Ref.1

Secondary structure

1

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380

Helix Strand Turn

Details...

Beta strand

5 – 11

7

Beta strand

17 – 20

4

Beta strand

28 – 33

6

Beta strand

35 – 38

4

Beta strand

40 – 42

3

Beta strand

48 – 50

3

Beta strand

55 – 58

4

Beta strand

62 – 64

3

Beta strand

115 – 118

4

Beta strand

137 – 143

7

Beta strand

147 – 153

7

Beta strand

156 – 161

6

Helix

162 – 164

3

Beta strand

165 – 167

3

Beta strand

196 – 204

9

Beta strand

210 – 213

4

Beta strand

222 – 226

5

Turn

230 – 232

3

Beta strand

234 – 239

6

Turn

240 – 242

3

Beta strand

243 – 248

6

Beta strand

251 – 254

4

Helix

292 – 302

11

Beta strand

307 – 312

6

Beta strand

314 – 316

3

Beta strand

320 – 324

5

Beta strand

327 – 329

3

Beta strand

331 – 338

8

Beta strand

341 – 344

4

Beta strand

347 – 351

5

Helix

352 – 361

10

Beta strand

364 – 366

3

Turn

368 – 370

3

Sequences

	Sequence		Length	Mass (Da)
	O43639 [UniParc]. Last modified May 10, 2002. Version 2. Checksum: 3A211085E46F4452	FASTA	380	42,915
	10 20 30 40 50 60 MTEEVIVIAK WDYTAQQDQE LDIKKNERLW LLDDSKTWWR VRNAANRTGY VPSNYVERKN 70 80 90 100 110 120 SLKKGSLVKN LKDTLGLGKT RRKTSARDAS PTPSTDAEYP ANGSGADRIY DLNIPAFVKF 130 140 150 160 170 180 AYVAEREDEL SLVKGSRVTV MEKCSDGWWR GSYNGQIGWF PSNYVLEEVD EAAAESPSFL 190 200 210 220 230 240 SLRKGASLSN GQGSRVLHVV QTLYPFSSVT EEELNFEKGE TMEVIEKPEN DPEWWKCKNA 250 260 270 280 290 300 RGQVGLVPKN YVVVLSDGPA LHPAHAPQIS YTGPSSSGRF AGREWYYGNV TRHQAECALN 310 320 330 340 350 360 ERGVEGDFLI RDSESSPSDF SVSLKASGKN KHFKVQLVDN VYCIGQRRFH TMDELVEHYK 370 380 KAPIFTSEHG EKLYLVRALQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of Nck family genes, chromosomal localization, expression, and signaling specificity." Chen M., She H., Davis E.M., Spicer C.M., Kim L., Ren R., LeBeau M.M., Li W. J. Biol. Chem. 273:25171-25178(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Nck-2, a novel Src homology2/3-containing adaptor protein that interacts with the LIM-only protein PINCH and components of growth factor receptor kinase-signaling pathways." Tu Y., Li F., Wu C. Mol. Biol. Cell 9:3367-3382(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH LIMS1. Tissue: Lung.
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases 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]. Tissue: Placenta and Uterus.
[5]	"Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck." Braverman L.E., Quilliam L.A. J. Biol. Chem. 274:5542-5549(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH EGFR; PAK1; PKN2 AND SOS1, PHOSPHORYLATION.
[6]	"Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: a role in cytoskeletal remodeling." Turner C.E., Brown M.C., Perrotta J.A., Riedy M.C., Nikolopoulos S.N., McDonald A.R., Bagrodia S., Thomas S.M., Leventhal P.S. J. Cell Biol. 145:851-863(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TGFB1I1.
[7]	"Identification and kinetic analysis of the interaction between Nck-2 and DOCK180." Tu Y., Kucik D.F., Wu C. FEBS Lett. 491:193-199(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DOCK1, MUTAGENESIS OF TRP-148 AND TRP-234.
[8]	"Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin." Hafizi S., Alindri F., Karlsson R., Dahlbaeck B. Biochem. Biophys. Res. Commun. 299:793-800(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AXL.
[9]	"Pinpointing phosphotyrosine-dependent interactions downstream of the collagen receptor DDR1." Koo D.H., McFadden C., Huang Y., Abdulhussein R., Friese-Hamim M., Vogel W.F. FEBS Lett. 580:15-22(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DDR1.
[10]	"Nck in a complex containing the catalytic subunit of protein phosphatase 1 regulates eukaryotic initiation factor 2alpha signaling and cell survival to endoplasmic reticulum stress." Latreille M., Larose L. J. Biol. Chem. 281:26633-26644(2006) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN COMPLEX WITH PP1 AND PPP1R15B, FUNCTION, SUBCELLULAR LOCATION.
[11]	"Phosphoproteome of resting human platelets." Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A. J. Proteome Res. 7:526-534(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-110, MASS SPECTROMETRY. Tissue: Platelet.
[12]	"Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening." Voss M., Lettau M., Janssen O. BMC Immunol. 10:53-53(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FASLG.
[13]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[14]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]	"Solution structure of the SH3 domain of the human cytoplasmic protein NCK2." RIKEN structural genomics initiative (RSGI) Submitted (JUL-2005) to the PDB data bank Cited for: STRUCTURE BY NMR OF 188-265.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF043119 mRNA. Translation: AAC04831.1.
AF047487 mRNA. Translation: AAC80284.1.
CH471127 Genomic DNA. Translation: EAX01753.1.
CH471127 Genomic DNA. Translation: EAX01754.1.
BC000103 mRNA. Translation: AAH00103.1.
BC007195 mRNA. Translation: AAH07195.1.

IPI

IPI00306531.

RefSeq

NP_001004720.1. NM_001004720.2.
NP_003572.2. NM_003581.4.

UniGene

Hs.529244.
Hs.735723.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1U5S	NMR	-	A	192-262	[»]
1WX6	NMR	-	A	188-265	[»]
1Z3K	NMR	-	A	283-380	[»]
2B86	NMR	-	A	1-59	[»]
2CIA	X-ray	1.45	A	284-380	[»]
2FRW	NMR	-	A	114-170	[»]
2FRY	NMR	-	A	198-256	[»]
2JXB	NMR	-	A	1-71	[»]
4E6R	X-ray	2.20	A/B	114-170	[»]

ProteinModelPortal

O43639.

ModBase

Search...

Protein-protein interaction databases

IntAct

O43639. 18 interactions.

MINT

MINT-190960.

STRING

9606.ENSP00000233154.

PTM databases

PhosphoSite

O43639.

Proteomic databases

PaxDb

O43639.

PRIDE

O43639.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000233154; ENSP00000233154; ENSG00000071051.
ENST00000393349; ENSP00000377018; ENSG00000071051.

GeneID

8440.

KEGG

hsa:8440.

UCSC

uc002tdg.3. human.

Organism-specific databases

CTD

8440.

GeneCards

GC02P106361.

HGNC

HGNC:7665. NCK2.

HPA

CAB016116.
HPA031004.

MIM

604930. gene.

neXtProt

NX_O43639.

PharmGKB

PA31467.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG261435.

HOGENOM

HOG000290684.

HOVERGEN

HBG000719.

InParanoid

O43639.

KO

K07365.

OMA

DGVYCIG.

OrthoDB

EOG4DR9CN.

PhylomeDB

O43639.

Enzyme and pathway databases

Pathway_Interaction_DB

ephrinbrevpathway. Ephrin B reverse signaling.
igf1_pathway. IGF1 pathway.
insulin_pathway. Insulin Pathway.
pdgfrbpathway. PDGFR-beta signaling pathway.
reelinpathway. Reelin signaling pathway.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_111155. Cell-Cell communication.

SignaLink

O43639.

Gene expression databases

ArrayExpress

O43639.

Bgee

O43639.

CleanEx

HS_NCK2.

Genevestigator

O43639.

GermOnline

ENSG00000071051. Homo sapiens.

Family and domain databases

Gene3D

3.30.505.10. 1 hit.

InterPro

IPR017304. Cytoplasmic_NCK.
IPR000980. SH2.
IPR001452. SH3_domain.
[Graphical view]

Pfam

PF00017. SH2. 1 hit.
PF00018. SH3_1. 3 hits.
[Graphical view]

PIRSF

PIRSF037874. Cytoplasmic_NCK. 1 hit.

PRINTS

PR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.

SMART

SM00252. SH2. 1 hit.
SM00326. SH3. 3 hits.
[Graphical view]

SUPFAM

SSF50044. SH3. 3 hits.

PROSITE

PS50001. SH2. 1 hit.
PS50002. SH3. 3 hits.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

O43639.

GenomeRNAi

8440.

NextBio

31578.

SOURCE

Search...

Entry information

Entry name

NCK2_HUMAN

Accession

Primary (citable) accession number: O43639
Secondary accession number(s): D3DVK1, Q9BWN9, Q9UIC3

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	May 10, 2002
Last modified:	May 29, 2013
This is version 131 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.