P51451 (BLK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tyrosine-protein kinase Blk
EC=2.7.10.2

Alternative name(s):
B lymphocyte kinase
p55-Blk

Gene names

Name:

BLK

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

General annotation (Comments)

Function	Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling. B-cell receptor (BCR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated coreceptors. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. Signaling through BLK plays an important role in transmitting signals through surface immunoglobulins and supports the pro-B to pre-B transition, as well as the signaling for growth arrest and apoptosis downstream of B-cell receptor. Specifically binds and phosphorylates CD79A at 'Tyr-188'and 'Tyr-199', as well as CD79B at 'Tyr-196' and 'Tyr-207'. Phosphorylates also the immunoglobulin G receptors FCGR2A, FCGR2B and FCGR2C. With FYN and LYN, plays an essential role in pre-B-cell receptor (pre-BCR)-mediated NF-kappa-B activation. Contributes also to BTK activation by indirectly stimulating BTK intramolecular autophosphorylation. In pancreatic islets, acts as a modulator of beta-cells function through the up-regulation of PDX1 and NKX6-1 and consequent stimulation of insulin secretion in response to glucose. Ref.7 Ref.10
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	Antibody-mediated surface engagement of the B-cell antigen receptor (BCR) which results in the phosphorylation of BLK on tyrosine residues, stimulates the enzymatic activity By similarity.
Subunit structure	Interacts with CBL (via SH2 domain). Interacts with CD79A and CD79B (via SH2 domain) By similarity. Ref.6
Subcellular location	Cell membrane; Lipid-anchor By similarity. Note: Present and active in lipid rafts. Membrane location is required for the phosphorylation of CD79A and CD79B By similarity. Ref.9
Tissue specificity	Expressed in lymphatic organs, pancreatic islets, Leydig cells, striate ducts of salivary glands and hair follicles. Ref.10
Induction	Expression is under the control of NF-kappa-B as well as the B-cell specific transcription factors PAX5 and EBF1. Ref.8
Post-translational modification	Phosphorylated on tyrosine residues after antibody-mediated surface engagement of the B-cell antigen receptor (BCR) By similarity. Ref.9 Ubiquitination of activated BLK by the UBE3A ubiquitin protein ligase leads to its degradation by the ubiquitin-proteasome pathway By similarity.
Involvement in disease	Maturity-onset diabetes of the young 11 (MODY11) [MIM:613375]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Disease	Diabetes mellitus
Domain	SH2 domain SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Lipoprotein Myristate Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	B cell receptor signaling pathway Inferred from direct assay PubMed 876631. Source: UniProtKB intracellular protein kinase cascade Traceable author statement PubMed 2404338. Source: ProtInc positive regulation of insulin secretion Inferred from mutant phenotype Ref.10. Source: UniProtKB
Cellular_component	plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW non-membrane spanning protein tyrosine kinase activity Inferred from direct assay PubMed 876631. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 505	505	Tyrosine-protein kinase Blk		PRO_0000088061
Regions
	Domain	58 – 118	61	SH3
	Domain	124 – 220	97	SH2
	Domain	241 – 494	254	Protein kinase
	Nucleotide binding	247 – 255	9	ATP By similarity
Sites
	Active site	360	1	Proton acceptor By similarity
	Binding site	269	1	ATP By similarity
Amino acid modifications
	Modified residue	389	1	Phosphotyrosine; by autocatalysis By similarity
	Lipidation	2	1	N-myristoyl glycine By similarity
Natural variations
	Natural variant	48	1	T → I. Ref.12 Corresponds to variant rs35339715 [ dbSNP | Ensembl ].		VAR_041672
	Natural variant	71	1	A → T Associated with MODY11; reduces the enhancing effect of BLK on insulin secretion; reduces the inducing effect of BLK on the expression of PDX1 and NKX6-1; found as somatic mutation in a colorectal adenocarcinoma sample. Ref.10 Ref.12 Corresponds to variant rs55758736 [ dbSNP | Ensembl ].		VAR_041673
Experimental info
	Sequence conflict	287	1	V → M in CAA83965. Ref.1
	Sequence conflict	407	1	I → Y in AAB33265. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P51451 [UniParc]. Last modified August 21, 2007. Version 3. Checksum: B5F739BEF8389176	FASTA	505	57,706
	10 20 30 40 50 60 MGLVSSKKPD KEKPIKEKDK GQWSPLKVSA QDKDAPPLPP LVVFNHLTPP PPDEHLDEDK 70 80 90 100 110 120 HFVVALYDYT AMNDRDLQML KGEKLQVLKG TGDWWLARSL VTGREGYVPS NFVARVESLE 130 140 150 160 170 180 MERWFFRSQG RKEAERQLLA PINKAGSFLI RESETNKGAF SLSVKDVTTQ GELIKHYKIR 190 200 210 220 230 240 CLDEGGYYIS PRITFPSLQA LVQHYSKKGD GLCQRLTLPC VRPAPQNPWA QDEWEIPRQS 250 260 270 280 290 300 LRLVRKLGSG QFGEVWMGYY KNNMKVAIKT LKEGTMSPEA FLGEANVMKA LQHERLVRLY 310 320 330 340 350 360 AVVTKEPIYI VTEYMARGCL LDFLKTDEGS RLSLPRLIDM SAQIAEGMAY IERMNSIHRD 370 380 390 400 410 420 LRAANILVSE ALCCKIADFG LARIIDSEYT AQEGAKFPIK WTAPEAIHFG VFTIKADVWS 430 440 450 460 470 480 FGVLLMEVVT YGRVPYPGMS NPEVIRNLER GYRMPRPDTC PPELYRGVIA ECWRSRPEER 490 500 PTFEFLQSVL EDFYTATERQ YELQP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning, characterization, and chromosomal localization of a human lymphoid tyrosine kinase related to murine Blk." Islam K.B., Rabbani H., Larsson C., Sanders R., Smith C.I. J. Immunol. 154:1265-1272(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Molecular cloning and chromosomal localization of the human homologue of a B-lymphocyte specific protein tyrosine kinase (blk)." Drebin J.A., Hartzell S.W., Griffin C., Campbell M.J., Niederhuber J.E. Oncogene 10:477-486(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Spleen.
[4]	Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases 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]. Tissue: Blood and Lymph.
[6]	"The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor." Donovan J.A., Wange R.L., Langdon W.Y., Samelson L.E. J. Biol. Chem. 269:22921-22924(1994) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CBL.
[7]	"In vivo and in vitro specificity of protein tyrosine kinases for immunoglobulin G receptor (FcgammaRII) phosphorylation." Bewarder N., Weinrich V., Budde P., Hartmann D., Flaswinkel H., Reth M., Frey J. Mol. Cell. Biol. 16:4735-4743(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF FCGR2A; FCGR2B AND FCGR2C.
[8]	"Early B cell factor is an activator of the B lymphoid kinase promoter in early B cell development." Akerblad P., Sigvardsson M. J. Immunol. 163:5453-5461(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[9]	"IgA Fc receptor (FcalphaR) cross-linking recruits tyrosine kinases, phosphoinositide kinases and serine/threonine kinases to glycolipid rafts." Lang M.L., Chen Y.W., Shen L., Gao H., Lang G.A., Wade T.K., Wade W.F. Biochem. J. 364:517-525(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, SUBCELLULAR LOCATION.
[10]	"Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction." Borowiec M., Liew C.W., Thompson R., Boonyasrisawat W., Hu J., Mlynarski W.M., El Khattabi I., Kim S.H., Marselli L., Rich S.S., Krolewski A.S., Bonner-Weir S., Sharma A., Sale M., Mychaleckyj J.C., Kulkarni R.N., Doria A. Proc. Natl. Acad. Sci. U.S.A. 106:14460-14465(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS REGULATOR OF INSULIN SECRETION, TISSUE SPECIFICITY, INVOLVEMENT IN MODY11, VARIANT THR-71, CHARACTERIZATION OF VARIANT THR-71.
[11]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ILE-48; THR-71 AND THR-71.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	Z33998 mRNA. Translation: CAA83965.1. S76617 mRNA. Translation: AAB33265.1. AK313751 mRNA. Translation: BAG36491.1. CH471157 Genomic DNA. Translation: EAW65617.1. BC007371 mRNA. Translation: AAH07371.1. BC032413 mRNA. Translation: AAH32413.1.
IPI	IPI00941870.
PIR	I37206.
RefSeq	NP_001706.2. NM_001715.2.
UniGene	Hs.146591.
3D structure databases
ProteinModelPortal	P51451.
ModBase	Search...
Protein-protein interaction databases
IntAct	P51451. 2 interactions.
MINT	MINT-1494192.
STRING	9606.ENSP00000259089.
PTM databases
PhosphoSite	P51451.
Polymorphism databases
DMDM	158936749.
Proteomic databases
PaxDb	P51451.
PRIDE	P51451.
Protocols and materials databases
DNASU	640.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000259089; ENSP00000259089; ENSG00000136573.
GeneID	640.
KEGG	hsa:640.
UCSC	uc003wty.3. human.
Organism-specific databases
CTD	640.
GeneCards	GC08P011388.
H-InvDB	HIX0007315. HIX0168887.
HGNC	HGNC:1057. BLK.
HPA	CAB005093.
MIM	191305. gene. 613375. phenotype.
neXtProt	NX_P51451.
Orphanet	552. MODY syndrome.
PharmGKB	PA25368.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233858.
HOVERGEN	HBG008761.
InParanoid	P51451.
KO	K08890.
PhylomeDB	P51451.
Enzyme and pathway databases
BRENDA	2.7.10.2. 2681.
Pathway_Interaction_DB	alphasynuclein_pathway. Alpha-synuclein signaling. amb2_neutrophils_pathway. amb2 Integrin signaling. pi3kcipathway. Class I PI3K signaling events. epha_fwdpathway. EPHA forward signaling. ephrinbrevpathway. Ephrin B reverse signaling. glypican_1pathway. Glypican 1 network. pdgfrbpathway. PDGFR-beta signaling pathway. p38alphabetapathway. Regulation of p38-alpha and p38-beta. ptp1bpathway. Signaling events mediated by PTP1B. txa2pathway. Thromboxane A2 receptor signaling.
Reactome	REACT_6900. Immune System.
SignaLink	P51451.
Gene expression databases
ArrayExpress	P51451.
Bgee	P51451.
CleanEx	HS_BLK.
Genevestigator	P51451.
GermOnline	ENSG00000136573. Homo sapiens.
Family and domain databases
Gene3D	3.30.505.10. 1 hit.
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR000980. SH2. IPR001452. SH3_domain. IPR020635. Tyr_kinase_cat_dom. [Graphical view]
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF00017. SH2. 1 hit. PF00018. SH3_1. 1 hit. [Graphical view]
PRINTS	PR00401. SH2DOMAIN. PR00452. SH3DOMAIN. PR00109. TYRKINASE.
SMART	SM00252. SH2. 1 hit. SM00326. SH3. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit. SSF50044. SH3. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. False negative. PS50001. SH2. 1 hit. PS50002. SH3. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P51451.
ChEMBL	CHEMBL2250.
ChiTaRS	BLK. human.
GenomeRNAi	640.
NextBio	2596.
SOURCE	Search...

Entry information

Entry name

BLK_HUMAN

Accession

Primary (citable) accession number: P51451
Secondary accession number(s): Q16291, Q96IN1

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	August 21, 2007
Last modified:	May 29, 2013
This is version 126 of the entry and version 3 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.