Q8WV28 (BLNK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
B-cell linker protein

Alternative name(s):
B-cell adapter containing a SH2 domain protein
B-cell adapter containing a Src homology 2 domain protein
Cytoplasmic adapter protein
Src homology 2 domain-containing leukocyte protein of 65 kDa
Short name=SLP-65

Gene names

Name:	BLNK
Synonyms:	BASH, SLP65

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	456 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Functions as a central linker protein, downstream of the B-cell receptor (BCR), bridging the SYK kinase to a multitude of signaling pathways and regulating biological outcomes of B-cell function and development. Plays a role in the activation of ERK/EPHB2, MAP kinase p38 and JNK. Modulates AP1 activation. Important for the activation of NF-kappa-B and NFAT. Plays an important role in BCR-mediated PLCG1 and PLCG2 activation and Ca2+ mobilization and is required for trafficking of the BCR to late endosomes. However, does not seem to be required for pre-BCR-mediated activation of MAP kinase and phosphatidyl-inositol 3 (PI3) kinase signaling. May be required for the RAC1-JNK pathway. Plays a critical role in orchestrating the pro-B cell to pre-B cell transition. May play an important role in BCR-induced B-cell apoptosis. Ref.1 Ref.2 Ref.8 Ref.9
Subunit structure	Associates with PLCG1, VAV1 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with VAV3, PLCG2 and GRB2. Interacts through its SH2 domain with CD79A. Interacts (via SH2 domain) with SYK; phosphorylated and activated by SYK. Interacts with SCIMP. Ref.1 Ref.6 Ref.9 Ref.10 Ref.11
Subcellular location	Cytoplasm. Cell membrane. Note: BCR activation results in the translocation to membrane fraction. Ref.1
Tissue specificity	Expressed in B-cell lineage and fibroblast cell lines (at protein level). Highest levels of expression in the spleen, with lower levels in the liver, kidney, pancreas, small intestines and colon.
Post-translational modification	Following BCR activation, phosphorylated on tyrosine residues by SYK and LYN. When phosphorylated, serves as a scaffold to assemble downstream targets of antigen activation, including PLCG1, VAV1, GRB2 and NCK1. Phosphorylation of Tyr-84, Tyr-178 and Tyr-189 facilitates PLCG1 binding. Phosphorylation of Tyr-96 facilitates BTK binding. Phosphorylation of Tyr-72 facilitates VAV1 and NCK1 binding. Phosphorylation is required for both Ca2+ and MAPK signaling pathways. Ref.1 Ref.7
Involvement in disease	Agammaglobulinemia 4 (AGM4) [MIM:613502]: A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.2
Sequence similarities	Contains 1 SH2 domain.

Ontologies

Keywords
Biological process	B-cell activation
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing
Domain	SH2 domain
PTM	Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	B cell differentiation Non-traceable author statement Ref.2. Source: UniProtKB humoral immune response Traceable author statement Ref.1. Source: ProtInc inflammatory response Traceable author statement Ref.1. Source: ProtInc intracellular signal transduction Inferred from direct assay Ref.6. Source: UniProtKB
Cellular_component	cytosol Traceable author statement. Source: Reactome plasma membrane Traceable author statement. Source: Reactome
Molecular_function	SH3/SH2 adaptor activity Inferred from direct assay Ref.1. Source: UniProtKB transmembrane receptor protein tyrosine kinase adaptor activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q8WV28-1)

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.

Isoform 2 (identifier: Q8WV28-2)

The sequence of this isoform differs from the canonical sequence as follows:
     203-225: Missing.

Isoform 3 (identifier: Q8WV28-3)

The sequence of this isoform differs from the canonical sequence as follows:
     366-417: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 456	456	B-cell linker protein		PRO_0000064940
Regions
	Domain	346 – 453	108	SH2
	Compositional bias	98 – 260	163	Pro-rich
Amino acid modifications
	Modified residue	72	1	Phosphotyrosine; by SYK Ref.7
	Modified residue	84	1	Phosphotyrosine; by SYK Ref.7
	Modified residue	96	1	Phosphotyrosine; by SYK Ref.7
	Modified residue	178	1	Phosphotyrosine; by SYK Ref.7
	Modified residue	189	1	Phosphotyrosine; by SYK Ref.7
Natural variations
	Alternative sequence	203 – 225	23	Missing in isoform 2.		VSP_016178
	Alternative sequence	366 – 417	52	Missing in isoform 3.		VSP_045324
Experimental info
	Mutagenesis	72	1	Y → F: Significant phosphorylation reduction; when associated with F-84; F-96 and F-178. Ref.1 Ref.7
	Mutagenesis	84	1	Y → F: Significant phosphorylation reduction; when associated with F-72; F-96 and F-178. Ref.1 Ref.7
	Mutagenesis	96	1	Y → F: Significant phosphorylation reduction; when associated with F-72; F-84 and F-178. Ref.1 Ref.7
	Mutagenesis	178	1	Y → F: Significant phosphorylation reduction; when associated with F-72; F-84 and F-96. Ref.1 Ref.7
	Sequence conflict	62	1	E → Q in AAH18906. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 22, 2005. Version 2. Checksum: 95F1D5485D03D397	FASTA	456	50,466
	10 20 30 40 50 60 MDKLNKITVP ASQKLRQLQK MVHDIKNNEG GIMNKIKKLK VKAPPSVPRR DYASESPADE 70 80 90 100 110 120 EEQWSDDFDS DYENPDEHSD SEMYVMPAEE NADDSYEPPP VEQETRPVHP ALPFARGEYI 130 140 150 160 170 180 DNRSSQRHSP PFSKTLPSKP SWPSEKARLT STLPALTALQ KPQVPPKPKG LLEDEADYVV 190 200 210 220 230 240 PVEDNDENYI HPTESSSPPP EKAPMVNRST KPNSSTPASP PGTASGRNSG AWETKSPPPA 250 260 270 280 290 300 APSPLPRAGK KPTTPLKTTP VASQQNASSV CEEKPIPAER HRGSSHRQEA VQSPVFPPAQ 310 320 330 340 350 360 KQIHQKPIPL PRFTEGGNPT VDGPLPSFSS NSTISEQEAG VLCKPWYAGA CDRKSAEEAL 370 380 390 400 410 420 HRSNKDGSFL IRKSSGHDSK QPYTLVVFFN KRVYNIPVRF IEATKQYALG RKKNGEEYFG 430 440 450 SVAEIIRNHQ HSPLVLIDSQ NNTKDSTRLK YAVKVS
	Isoform 2 [UniParc]. Checksum: 0B36FE9FCF5DC7DC	FASTA	433	48,229
	10 20 30 40 50 60 MDKLNKITVP ASQKLRQLQK MVHDIKNNEG GIMNKIKKLK VKAPPSVPRR DYASESPADE 70 80 90 100 110 120 EEQWSDDFDS DYENPDEHSD SEMYVMPAEE NADDSYEPPP VEQETRPVHP ALPFARGEYI 130 140 150 160 170 180 DNRSSQRHSP PFSKTLPSKP SWPSEKARLT STLPALTALQ KPQVPPKPKG LLEDEADYVV 190 200 210 220 230 240 PVEDNDENYI HPTESSSPPP EKGRNSGAWE TKSPPPAAPS PLPRAGKKPT TPLKTTPVAS 250 260 270 280 290 300 QQNASSVCEE KPIPAERHRG SSHRQEAVQS PVFPPAQKQI HQKPIPLPRF TEGGNPTVDG 310 320 330 340 350 360 PLPSFSSNST ISEQEAGVLC KPWYAGACDR KSAEEALHRS NKDGSFLIRK SSGHDSKQPY 370 380 390 400 410 420 TLVVFFNKRV YNIPVRFIEA TKQYALGRKK NGEEYFGSVA EIIRNHQHSP LVLIDSQNNT 430 KDSTRLKYAV KVS
	Isoform 3 [UniParc]. Checksum: 2288B35E399683F4	FASTA	404	44,451
	10 20 30 40 50 60 MDKLNKITVP ASQKLRQLQK MVHDIKNNEG GIMNKIKKLK VKAPPSVPRR DYASESPADE 70 80 90 100 110 120 EEQWSDDFDS DYENPDEHSD SEMYVMPAEE NADDSYEPPP VEQETRPVHP ALPFARGEYI 130 140 150 160 170 180 DNRSSQRHSP PFSKTLPSKP SWPSEKARLT STLPALTALQ KPQVPPKPKG LLEDEADYVV 190 200 210 220 230 240 PVEDNDENYI HPTESSSPPP EKAPMVNRST KPNSSTPASP PGTASGRNSG AWETKSPPPA 250 260 270 280 290 300 APSPLPRAGK KPTTPLKTTP VASQQNASSV CEEKPIPAER HRGSSHRQEA VQSPVFPPAQ 310 320 330 340 350 360 KQIHQKPIPL PRFTEGGNPT VDGPLPSFSS NSTISEQEAG VLCKPWYAGA CDRKSAEEAL 370 380 390 400 HRSNKYFGSV AEIIRNHQHS PLVLIDSQNN TKDSTRLKYA VKVS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"BLNK: a central linker protein in B cell activation." Fu C., Turck C.W., Kurosaki T., Chan A.C. Immunity 9:93-103(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), PROTEIN SEQUENCE OF 7-20; 140-146; 237-248; 250-257; 366-373 AND 392-405, FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PLCG1; VAV1; GRB2 AND NCK1, ALTERNATIVE SPLICING, PHOSPHORYLATION, MUTAGENESIS OF TYR-72; TYR-84; TYR-96 AND TYR-178.
[2]	"An essential role for BLNK in human B cell development." Minegishi Y., Rohrer J., Coustan-Smith E., Lederman H.M., Pappu R., Campana D., Chan A.C., Conley M.E. Science 286:1954-1957(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2), FUNCTION IN B-CELL DEVELOPMENT, INVOLVEMENT IN AGM4.
[3]	"SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells." Sprangers M., Feldhahn N., Liedtke S., Jumaa H., Siebert R., Muschen M. Oncogene 25:5180-5186(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
[4]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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] (ISOFORM 1). Tissue: B-cell.
[6]	"Identification of two tyrosine phosphoproteins, pp70 and pp68, which interact with phospholipase Cgamma, Grb2, and Vav after B cell antigen receptor activation." Fu C., Chan A.C. J. Biol. Chem. 272:27362-27368(1997) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PLCG1; VAV1; GRB2 AND NCK1.
[7]	"BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins." Chiu C.W., Dalton M., Ishiai M., Kurosaki T., Chan A.C. EMBO J. 21:6461-6472(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT TYR-72; TYR-84; TYR-96; TYR-178 AND TYR-189 BY SYK, MUTAGENESIS OF TYR-72; TYR-84 AND TYR-96.
[8]	"Deficiency of BLNK hampers PLC-gamma2 phosphorylation and Ca2+ influx induced by the pre-B-cell receptor in human pre-B cells." Taguchi T., Kiyokawa N., Takenouch H., Matsui J., Tang W.-R., Nakajima H., Suzuki K., Shiozawa Y., Saito M., Katagiri Y.U., Takahashi T., Karasuyama H., Matsuo Y., Okita H., Fujimoto J. Immunology 112:575-582(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PLCG1 ACTIVATION AND CALCIUM MOBILIZATION.
[9]	"Human SLP-65 isoforms contribute differently to activation and apoptosis of B lymphocytes." Grabbe A., Wienands J. Blood 108:3761-3768(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH GRB2.
[10]	"The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development." Kulathu Y., Hobeika E., Turchinovich G., Reth M. EMBO J. 27:1333-1344(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SYK.
[11]	"SCIMP, a transmembrane adapter protein involved in major histocompatibility complex class II signaling." Draber P., Vonkova I., Stepanek O., Hrdinka M., Kucova M., Skopcova T., Otahal P., Angelisova P., Horejsi V., Yeung M., Weiss A., Brdicka T. Mol. Cell. Biol. 31:4550-4562(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SCIMP.
+	Additional computationally mapped references.

Web resources

BLNKbase

BLNK mutation db

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF068180 mRNA. Translation: AAC39936.1. AF068181 mRNA. Translation: AAC39937.1. AF180756 , AF180740, AF180741, AF180742, AF180743, AF180744, AF180745, AF180746, AF180747, AF180748, AF180749, AF180750, AF180751, AF180752, AF180753, AF180754, AF180755 Genomic DNA. Translation: AAF20382.1. AF180756 , AF180740, AF180741, AF180742, AF180743, AF180744, AF180745, AF180746, AF180748, AF180749, AF180750, AF180751, AF180752, AF180753, AF180754, AF180755 Genomic DNA. Translation: AAF20383.1. AM180337 mRNA. Translation: CAJ55331.1. AC021037 Genomic DNA. No translation available. BC018906 mRNA. Translation: AAH18906.1.
IPI	IPI00002434. IPI00004549.
RefSeq	NP_001107566.1. NM_001114094.1. NP_001245369.1. NM_001258440.1. NP_037446.1. NM_013314.3.
UniGene	Hs.665244.
3D structure databases
ProteinModelPortal	Q8WV28.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q8WV28. 1 interaction.
MINT	MINT-110179.
STRING	9606.ENSP00000224337.
PTM databases
PhosphoSite	Q8WV28.
Polymorphism databases
DMDM	82592659.
Proteomic databases
PaxDb	Q8WV28.
PRIDE	Q8WV28.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000224337; ENSP00000224337; ENSG00000095585. ENST00000371176; ENSP00000360218; ENSG00000095585. ENST00000413476; ENSP00000397487; ENSG00000095585. ENST00000574329; ENSP00000461050; ENSG00000262509. ENST00000574984; ENSP00000460444; ENSG00000262509.
GeneID	29760.
KEGG	hsa:29760.
UCSC	uc001kls.4. human. uc001klt.4. human.
Organism-specific databases
CTD	29760.
GeneCards	GC10M097941.
HGNC	HGNC:14211. BLNK.
HPA	CAB009333. CAB016291. HPA038309. HPA038310.
MIM	604515. gene. 613502. phenotype.
neXtProt	NX_Q8WV28.
Orphanet	33110. Autosomal agammaglobulinemia.
PharmGKB	PA25371.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG44661.
HOGENOM	HOG000088646.
HOVERGEN	HBG053147.
InParanoid	Q8WV28.
KO	K07371.
OMA	PFARGEY.
OrthoDB	EOG46T31H.
PhylomeDB	Q8WV28.
Enzyme and pathway databases
Pathway_Interaction_DB	bcr_5pathway. BCR signaling pathway. pi3kcipathway. Class I PI3K signaling events.
Reactome	REACT_6900. Immune System.
Gene expression databases
ArrayExpress	Q8WV28.
Bgee	Q8WV28.
CleanEx	HS_BLNK.
Genevestigator	Q8WV28.
GermOnline	ENSG00000095585. Homo sapiens.
Family and domain databases
Gene3D	3.30.505.10. 1 hit.
InterPro	IPR000980. SH2. [Graphical view]
Pfam	PF00017. SH2. 1 hit. [Graphical view]
SMART	SM00252. SH2. 1 hit. [Graphical view]
PROSITE	PS50001. SH2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	29760.
NextBio	52250.
SOURCE	Search...

Entry information

Entry name

BLNK_HUMAN

Accession

Primary (citable) accession number: Q8WV28
Secondary accession number(s): O75498, O75499, Q2MD49

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 22, 2005
Last sequence update:	November 22, 2005
Last modified:	May 1, 2013
This is version 97 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.