BLNK_MOUSE
ID BLNK_MOUSE Reviewed; 457 AA.
AC Q9QUN3; O88504;
DT 22-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=B-cell linker protein;
DE AltName: Full=B-cell adapter containing a SH2 domain protein;
DE AltName: Full=B-cell adapter containing a Src homology 2 domain protein;
DE AltName: Full=Cytoplasmic adapter protein;
DE AltName: Full=Lymphocyte antigen 57;
DE AltName: Full=Src homology 2 domain-containing leukocyte protein of 65 kDa;
DE Short=Slp-65;
GN Name=Blnk; Synonyms=Bash, Ly57, Slp65;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9697839; DOI=10.1016/s1074-7613(00)80591-9;
RA Fu C., Turck C.W., Kurosaki T., Chan A.C.;
RT "BLNK: a central linker protein in B cell activation.";
RL Immunity 9:93-103(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 7-20; 147-161; 170-186;
RP 356-366 AND 393-412, FUNCTION, TISSUE SPECIFICITY, PHOSPHORYLATION, AND
RP INTERACTION WITH VAV1 AND GRB2.
RC STRAIN=BALB/cJ; TISSUE=Lymphoid tissue;
RX PubMed=9705962; DOI=10.1084/jem.188.4.791;
RA Wienands J., Schweikert J., Wollschied B., Jumaa H., Nielsen P.J., Reth M.;
RT "SLP-65: a new signaling component in B lymphocytes which requires
RT expression of the antigen receptor for phosphorylation.";
RL J. Exp. Med. 188:791-795(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Okamoto N., Hayashi K., Tsuji S., Goitsuka R., Kitamura D.;
RT "BASH: B lymphocyte adaptor protein containing SH2 domain.";
RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Nielsen P.J., Guenet J.-L.;
RT "The murine SLP-65 gene.";
RL Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=129; TISSUE=Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP INTERACTION WITH CD79A, AND MUTAGENESIS OF ARG-373.
RX PubMed=11449366;
RX DOI=10.1002/1521-4141(200107)31:7<2126::aid-immu2126>3.0.co;2-o;
RA Engels N., Wollscheid B., Wienands J.;
RT "Association of SLP-65/BLNK with the B cell antigen receptor through a non-
RT ITAM tyrosine of Ig-alpha.";
RL Eur. J. Immunol. 31:2126-2134(2001).
RN [7]
RP INTERACTION WITH CD79A.
RX PubMed=11859098; DOI=10.4049/jimmunol.168.5.2127;
RA Siemasko K., Skaggs B.J., Kabak S., Williamson E., Brown B.K., Song W.,
RA Clark M.R.;
RT "Receptor-facilitated antigen presentation requires the recruitment of B
RT cell linker protein to Igalpha.";
RL J. Immunol. 168:2127-2138(2002).
RN [8]
RP INTERACTION WITH CD79A.
RX PubMed=11909947; DOI=10.1128/mcb.22.8.2524-2535.2002;
RA Kabak S., Skaggs B.J., Gold M.R., Affolter M., West K.L., Foster M.S.,
RA Siemasko K., Chan A.C., Aebersold R., Clark M.R.;
RT "The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell
RT antigen receptor to distal signaling pathways.";
RL Mol. Cell. Biol. 22:2524-2535(2002).
RN [9]
RP FUNCTION IN PRO-B CELL TO PRE-B CELL TRANSITION, AND MUTAGENESIS OF TYR-52
RP AND TYR-96.
RX PubMed=12761551; DOI=10.1038/nature01608;
RA Jumaa H., Bossaller L., Portugal K., Storch B., Lotz M., Flemming A.,
RA Schrappe M., Postila V., Riikonen P., Pelkonen J., Niemeyer C.M., Reth M.;
RT "Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic
RT leukaemia.";
RL Nature 423:452-456(2003).
RN [10]
RP FUNCTION IN SYK ACTIVATION, INTERACTION WITH SYK, AND MUTAGENESIS OF
RP ARG-373.
RX PubMed=18369315; DOI=10.1038/emboj.2008.62;
RA Kulathu Y., Hobeika E., Turchinovich G., Reth M.;
RT "The kinase Syk as an adaptor controlling sustained calcium signalling and
RT B-cell development.";
RL EMBO J. 27:1333-1344(2008).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [12]
RP INTERACTION WITH SCIMP.
RX PubMed=21930792; DOI=10.1128/mcb.05817-11;
RA Draber P., Vonkova I., Stepanek O., Hrdinka M., Kucova M., Skopcova T.,
RA Otahal P., Angelisova P., Horejsi V., Yeung M., Weiss A., Brdicka T.;
RT "SCIMP, a transmembrane adapter protein involved in major
RT histocompatibility complex class II signaling.";
RL Mol. Cell. Biol. 31:4550-4562(2011).
RN [13]
RP INTERACTION WITH SCIMP.
RX PubMed=28290451; DOI=10.1038/icb.2017.10;
RA Luo L., Tong S.J., Wall A.A., Khromykh T., Sweet M.J., Stow J.L.;
RT "Development of SH2 probes and pull-down assays to detect pathogen-induced,
RT site-specific tyrosine phosphorylation of the TLR adaptor SCIMP.";
RL Immunol. Cell Biol. 95:564-570(2017).
RN [14]
RP STRUCTURE BY NMR OF 328-457.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the SH2 domain from mouse B-cell linker protein
RT BLNK.";
RL Submitted (APR-2008) to the PDB data bank.
CC -!- FUNCTION: Functions as a central linker protein, downstream of the B-
CC cell receptor (BCR), bridging the SYK kinase to a multitude of
CC signaling pathways and regulating biological outcomes of B-cell
CC function and development. Plays a role in the activation of ERK/EPHB2,
CC MAP kinase p38 and JNK. Modulates AP1 activation. Important for the
CC activation of NF-kappa-B and NFAT. Plays an important role in BCR-
CC mediated PLCG1 and PLCG2 activation and Ca(2+) mobilization and is
CC required for trafficking of the BCR to late endosomes. However, does
CC not seem to be required for pre-BCR-mediated activation of MAP kinase
CC and phosphatidyl-inositol 3 (PI3) kinase signaling. May be required for
CC the RAC1-JNK pathway. Plays a critical role in orchestrating the pro-B
CC cell to pre-B cell transition. May play an important role in BCR-
CC induced B-cell apoptosis. {ECO:0000269|PubMed:12761551,
CC ECO:0000269|PubMed:18369315, ECO:0000269|PubMed:9705962}.
CC -!- SUBUNIT: Associates with PLCG1, VAV1 and NCK1 in a B-cell antigen
CC receptor-dependent fashion. Interacts with VAV3, PLCG2 and GRB2 (By
CC similarity). Interacts through its SH2 domain with CD79A. Interacts
CC (via SH2 domain) with SYK; phosphorylated and activated by SYK.
CC Interacts (via SH2 domain) with SCIMP; this interaction is dependent on
CC phosphorylation of SCIMP 'Tyr-120' (PubMed:21930792, PubMed:28290451).
CC {ECO:0000250, ECO:0000269|PubMed:11449366, ECO:0000269|PubMed:11859098,
CC ECO:0000269|PubMed:11909947, ECO:0000269|PubMed:18369315,
CC ECO:0000269|PubMed:21930792, ECO:0000269|PubMed:28290451,
CC ECO:0000269|PubMed:9705962}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane
CC {ECO:0000250}. Note=BCR activation results in the translocation to
CC membrane fraction. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed in the spleen and weakly in thymus, no
CC expression was seen in liver, testis, or brain. Expressed in B-cell
CC lines representing different developmental stages from the pre-B to the
CC plasma cell stage, but not in a T-cell or a fibroblast cell line.
CC {ECO:0000269|PubMed:9705962}.
CC -!- PTM: Following BCR activation, phosphorylated on tyrosine residues by
CC SYK and LYN. When phosphorylated, serves as a scaffold to assemble
CC downstream targets of antigen activation, including PLCG1, VAV1, GRB2
CC and NCK1. Phosphorylation of Tyr-84, Tyr-178 and Tyr-189 facilitates
CC PLCG1 binding. Phosphorylation of Tyr-72 facilitates VAV1 and NCK1
CC binding. Phosphorylation is required for both Ca(2+) and MAPK signaling
CC pathways (By similarity). Phosphorylation of Tyr-96 is required for the
CC binding of BTK. {ECO:0000250, ECO:0000269|PubMed:9705962}.
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DR EMBL; AF068182; AAC40206.1; -; mRNA.
DR EMBL; Y17159; CAA76666.1; -; mRNA.
DR EMBL; AB015290; BAA34944.1; -; mRNA.
DR EMBL; AJ298054; CAC18565.1; -; Genomic_DNA.
DR EMBL; BC059785; AAH59785.1; -; mRNA.
DR CCDS; CCDS37983.1; -.
DR RefSeq; NP_032554.2; NM_008528.4.
DR PDB; 2EO6; NMR; -; A=330-457.
DR PDBsum; 2EO6; -.
DR AlphaFoldDB; Q9QUN3; -.
DR SMR; Q9QUN3; -.
DR BioGRID; 201236; 5.
DR CORUM; Q9QUN3; -.
DR IntAct; Q9QUN3; 7.
DR MINT; Q9QUN3; -.
DR STRING; 10090.ENSMUSP00000057844; -.
DR iPTMnet; Q9QUN3; -.
DR PhosphoSitePlus; Q9QUN3; -.
DR MaxQB; Q9QUN3; -.
DR PaxDb; Q9QUN3; -.
DR PeptideAtlas; Q9QUN3; -.
DR PRIDE; Q9QUN3; -.
DR ProteomicsDB; 265305; -.
DR Antibodypedia; 3990; 761 antibodies from 42 providers.
DR DNASU; 17060; -.
DR Ensembl; ENSMUST00000054769; ENSMUSP00000057844; ENSMUSG00000061132.
DR GeneID; 17060; -.
DR KEGG; mmu:17060; -.
DR UCSC; uc008hll.1; mouse.
DR CTD; 29760; -.
DR MGI; MGI:96878; Blnk.
DR VEuPathDB; HostDB:ENSMUSG00000061132; -.
DR eggNOG; ENOG502QUXR; Eukaryota.
DR GeneTree; ENSGT00940000155715; -.
DR HOGENOM; CLU_043673_0_0_1; -.
DR InParanoid; Q9QUN3; -.
DR OMA; QEADLHC; -.
DR OrthoDB; 556782at2759; -.
DR PhylomeDB; Q9QUN3; -.
DR TreeFam; TF326567; -.
DR Reactome; R-MMU-983695; Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
DR BioGRID-ORCS; 17060; 1 hit in 72 CRISPR screens.
DR ChiTaRS; Blnk; mouse.
DR EvolutionaryTrace; Q9QUN3; -.
DR PRO; PR:Q9QUN3; -.
DR Proteomes; UP000000589; Chromosome 19.
DR RNAct; Q9QUN3; protein.
DR Bgee; ENSMUSG00000061132; Expressed in spleen and 120 other tissues.
DR ExpressionAtlas; Q9QUN3; baseline and differential.
DR Genevisible; Q9QUN3; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0016020; C:membrane; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0043274; F:phospholipase binding; ISO:MGI.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:1990782; F:protein tyrosine kinase binding; ISO:MGI.
DR GO; GO:0042169; F:SH2 domain binding; ISO:MGI.
DR GO; GO:0035591; F:signaling adaptor activity; ISO:MGI.
DR GO; GO:0042113; P:B cell activation; IEA:UniProtKB-KW.
DR GO; GO:0050853; P:B cell receptor signaling pathway; ISO:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR Pfam; PF00017; SH2; 1.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; B-cell activation; Cell membrane; Cytoplasm;
KW Direct protein sequencing; Membrane; Phosphoprotein; Reference proteome;
KW SH2 domain.
FT CHAIN 1..457
FT /note="B-cell linker protein"
FT /id="PRO_0000064941"
FT DOMAIN 347..454
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT REGION 36..306
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 58..76
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 124..140
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 207..223
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 72
FT /note="Phosphotyrosine; by SYK"
FT /evidence="ECO:0000250|UniProtKB:Q8WV28"
FT MOD_RES 84
FT /note="Phosphotyrosine; by SYK"
FT /evidence="ECO:0000250|UniProtKB:Q8WV28"
FT MOD_RES 96
FT /note="Phosphotyrosine; by SYK"
FT /evidence="ECO:0000250|UniProtKB:Q8WV28"
FT MOD_RES 178
FT /note="Phosphotyrosine; by SYK"
FT /evidence="ECO:0000250|UniProtKB:Q8WV28"
FT MOD_RES 189
FT /note="Phosphotyrosine; by SYK"
FT /evidence="ECO:0000250|UniProtKB:Q8WV28"
FT MUTAGEN 52
FT /note="Y->F: No effect on pre-BCR down-regulation."
FT /evidence="ECO:0000269|PubMed:12761551"
FT MUTAGEN 96
FT /note="Y->F: Fails to induce pre-BCR down-regulation,
FT leading to splenomegaly and leukemia."
FT /evidence="ECO:0000269|PubMed:12761551"
FT MUTAGEN 373
FT /note="R->L: Abolishes binding to CD79A and SYK."
FT /evidence="ECO:0000269|PubMed:11449366,
FT ECO:0000269|PubMed:18369315"
FT CONFLICT 333
FT /note="S -> L (in Ref. 1; AAC40206)"
FT /evidence="ECO:0000305"
FT CONFLICT 340
FT /note="A -> G (in Ref. 1; AAC40206)"
FT /evidence="ECO:0000305"
FT CONFLICT 356
FT /note="S -> F (in Ref. 1; AAC40206)"
FT /evidence="ECO:0000305"
FT CONFLICT 376
FT /note="S -> F (in Ref. 1; AAC40206)"
FT /evidence="ECO:0000305"
FT HELIX 334..340
FT /evidence="ECO:0007829|PDB:2EO6"
FT TURN 341..344
FT /evidence="ECO:0007829|PDB:2EO6"
FT STRAND 346..351
FT /evidence="ECO:0007829|PDB:2EO6"
FT HELIX 354..364
FT /evidence="ECO:0007829|PDB:2EO6"
FT STRAND 372..374
FT /evidence="ECO:0007829|PDB:2EO6"
FT STRAND 383..390
FT /evidence="ECO:0007829|PDB:2EO6"
FT STRAND 393..399
FT /evidence="ECO:0007829|PDB:2EO6"
FT TURN 403..406
FT /evidence="ECO:0007829|PDB:2EO6"
FT STRAND 410..412
FT /evidence="ECO:0007829|PDB:2EO6"
FT STRAND 420..422
FT /evidence="ECO:0007829|PDB:2EO6"
FT HELIX 423..432
FT /evidence="ECO:0007829|PDB:2EO6"
FT STRAND 440..442
FT /evidence="ECO:0007829|PDB:2EO6"
SQ SEQUENCE 457 AA; 50671 MW; 66C93D4FDDF9D260 CRC64;
MDKLNKITVP ASQKLRQLQK MVHDIKNNEG GIMDKIKKLK VKGPPSVPRR DYALDSPADE
EEQWSDDFDS DYENPDEHSD SEMYVMPAEE TGDDSYEPPP AEQQTRVVHP ALPFTRGEYV
DNRSSQRHSP PFSKTLPSKP SWPSAKARLA STLPAPNSLQ KPQVPPKPKD LLEDEADYVV
PVEDNDENYI HPRESSPPPA EKAPMVNRST KPNSSSKHMS PPGTVAGRNS GVWDSKSSLP
AAPSPLPRAG KKPATPLKTT PVPPLPNASN VCEEKPVPAE RHRGSSHRQD TVQSPVFPPT
QKPVHQKPVP LPRFPEAGSP AADGPFHSFP FNSTFADQEA ELLGKPWYAG ACDRKSAEEA
LHRSNKDGSF LIRKSSGHDS KQPYTLVAFF NKRVYNIPVR FIEATKQYAL GKKKNGEEYF
GSVVEIVNSH QHNPLVLIDS QNNTKDSTRL KYAVKVS
