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{{Infobox_gene}}
{{PBB_Controls
The '''B-cell linker''' protein is encoded by the ''BLNK'' [[gene]]<ref name="pmid9697839">{{Cite journal
| update_page = yes
| last1 = Fu | first1 = C.
| require_manual_inspection = no
| last2 = Turck | first2 = C. W.
| update_protein_box = yes
| last3 = Kurosaki | first3 = T.
| update_summary = yes
| last4 = Chan | first4 = A. C.
| update_citations = yes
| title = BLNK: A central linker protein in B cell activation
}}
| journal = Immunity
| volume = 9
| issue = 1
| pages = 93–103
| year = 1998
| pmid = 9697839 | doi=10.1016/S1074-7613(00)80591-9
}}</ref><ref name="entrez">{{cite web | title = Entrez Gene: BLNK B-cell linker| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29760| accessdate = }}</ref> and is an [[Signal transducing adaptor protein|adaptor protein]] also known as '''SLP-65''',<ref name="pmid9705962">{{Cite journal
| last1 = Wienands | first1 = J.
| last2 = Schweikert | first2 = J.
| last3 = Wollscheid | first3 = B.
| last4 = Jumaa | first4 = H.
| last5 = Nielsen | first5 = P. J.
| last6 = Reth | first6 = M.
| title = SLP-65: A new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation
| journal = The Journal of Experimental Medicine
| volume = 188
| issue = 4
| pages = 791–795
| year = 1998
| pmid = 9705962
| pmc = 2213353 | doi=10.1084/jem.188.4.791
}}</ref> '''BASH''',<ref name="pmid9834055">{{Cite journal
| last1 = Goitsuka | first1 = R.
| last2 = Fujimura | first2 = Y.
| last3 = Mamada | first3 = H.
| last4 = Umeda | first4 = A.
| last5 = Morimura | first5 = T.
| last6 = Uetsuka | first6 = K.
| last7 = Doi | first7 = K.
| last8 = Tsuji | first8 = S.
| last9 = Kitamura | first9 = D.
| title = BASH, a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius
| journal = Journal of Immunology
| volume = 161
| issue = 11
| pages = 5804–5808
| year = 1998
| pmid = 9834055
}}</ref> and '''BCA'''.<ref name="pmid9683264">{{Cite journal
| last1 = Gangi-Peterson | first1 = L.
| last2 = Peterson | first2 = S. N.
| last3 = Shapiro | first3 = L. H.
| last4 = Golding | first4 = A.
| last5 = Caricchio | first5 = R.
| last6 = Cohen | first6 = D. I.
| last7 = Margulies | first7 = D. H.
| last8 = Cohen | first8 = P. L.
| title = Bca: An activation-related B-cell gene
| journal = Molecular immunology
| volume = 35
| issue = 1
| pages = 55–63
| year = 1998
| pmid = 9683264 | doi=10.1016/s0161-5890(98)00008-x
}}</ref> BLNK is expressed in [[B cell]]s and [[macrophage]]s and plays a large role in [[B cell receptor]] signalling, in a fashion analogous to the role its paralogue [[lymphocyte cytosolic protein 2|SLP-76]] plays in [[T cell receptor]] signalling.<ref name="pmid16493428">{{Cite journal
| last1 = Koretzky | first1 = G. A.
| last2 = Abtahian | first2 = F.
| last3 = Silverman | first3 = M. A.
| doi = 10.1038/nri1750
| title = SLP76 and SLP65: Complex regulation of signalling in lymphocytes and beyond
| journal = Nature Reviews Immunology
| volume = 6
| issue = 1
| pages = 67–78
| year = 2006
| pmid = 16493428
| pmc =  
}}</ref> As it has no known intrinsic enzymatic activity, the function of BLNK is to temporally and spatially coordinate and regulate signalling effectors [[Upstream and downstream (transduction)|downstream]] of the [[B cell receptor]].


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==Function==
{{GNF_Protein_box
The function of BLNK was first illustrated in BLNK deficient DT40 cells, a [[chicken]] [[B-cell]] line, which exhibited an abrogated intracellular calcium mobilisation response and impaired activation of MAP kinases [[p38 mitogen-activated protein kinases|p38]], [[c-Jun N-terminal kinases|JNK]], and to a lesser degree [[Extracellular signal-regulated kinases|ERK]] upon B-cell receptor (BCR) activation as compared to wild type DT40 cells.<ref name="pmid10023776">{{Cite journal
| image =
| last1 = Ishiai | first1 = M.
| image_source =
| last2 = Kurosaki | first2 = M.
| PDB =  
| last3 = Pappu | first3 = R.
| Name = B-cell linker
| last4 = Okawa | first4 = K.
| HGNCid = 14211
| last5 = Ronko | first5 = I.
| Symbol = BLNK
| last6 = Fu | first6 = C.
| AltSymbols =; BASH; BLNK-s; Ly57; MGC111051; SLP-65; SLP65
| last7 = Shibata | first7 = M.
| OMIM = 604515
| last8 = Iwamatsu | first8 = A.
| ECnumber =
| last9 = Chan | first9 = A. C.
| Homologene = 32038
| last10 = Kurosaki | first10 = T.
| MGIid = 96878
| title = BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells
| GeneAtlas_image1 = PBB_GE_BLNK_207655_s_at_tn.png
| journal = Immunity
| Function = {{GNF_GO|id=GO:0005068 |text = transmembrane receptor protein tyrosine kinase adaptor protein activity}} {{GNF_GO|id=GO:0005070 |text = SH3/SH2 adaptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}}
| volume = 10
| Component = {{GNF_GO|id=GO:0005622 |text = intracellular}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| issue = 1
| Process = {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0006959 |text = humoral immune response}} {{GNF_GO|id=GO:0007242 |text = intracellular signaling cascade}} {{GNF_GO|id=GO:0007516 |text = hemocyte development}} {{GNF_GO|id=GO:0030183 |text = B cell differentiation}}
| pages = 117–125
| Orthologs = {{GNF_Ortholog_box
| year = 1999
    | Hs_EntrezGene = 29760
| pmid = 10023776 | doi=10.1016/S1074-7613(00)80012-6
    | Hs_Ensembl = ENSG00000095585
}}</ref> In [[knockout mouse|knockout mice]], BLNK deficiency results in a partial block in B-cell development,<ref name="pmid10591180">{{Cite journal
    | Hs_RefseqProtein = NP_037446
| last1 = Jumaa | first1 = H.
    | Hs_RefseqmRNA = NM_013314
| last2 = Wollscheid | first2 = B.
    | Hs_GenLoc_db =
| last3 = Mitterer | first3 = M.
    | Hs_GenLoc_chr = 10
| last4 = Wienands | first4 = J.
    | Hs_GenLoc_start = 97941453
| last5 = Reth | first5 = M.
    | Hs_GenLoc_end = 98021316
| last6 = Nielsen | first6 = P. J.
    | Hs_Uniprot = Q8WV28
| title = Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65
    | Mm_EntrezGene = 17060
| journal = Immunity
    | Mm_Ensembl = ENSMUSG00000061132
| volume = 11
    | Mm_RefseqmRNA = NM_008528
| issue = 5
    | Mm_RefseqProtein = NP_032554
| pages = 547–554
    | Mm_GenLoc_db =
| year = 1999
    | Mm_GenLoc_chr = 19
| pmid = 10591180 | doi=10.1016/S1074-7613(00)80130-2
    | Mm_GenLoc_start = 40982484
}}</ref><ref name="pmid10583957">{{Cite journal
    | Mm_GenLoc_end = 41025964
| last1 = Pappu | first1 = R.
    | Mm_Uniprot = Q9QUN3
| last2 = Cheng | first2 = A. M.
  }}
| last3 = Li | first3 = B.
}}
| last4 = Gong | first4 = Q.
'''B-cell linker''', also known as '''BLNK''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: BLNK B-cell linker| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29760| accessdate = }}</ref>
| last5 = Chiu | first5 = C.
| last6 = Griffin | first6 = N.
| last7 = White | first7 = M.
| last8 = Sleckman | first8 = B. P.
| last9 = Chan | first9 = A. C.
| title = Requirement for B cell linker protein (BLNK) in B cell development
| journal = Science
| volume = 286
| issue = 5446
| pages = 1949–1954
| year = 1999
| pmid = 10583957 | doi=10.1126/science.286.5446.1949
}}</ref> and in humans BLNK deficiency results in a much more profound block in B-cell development.<ref name="pmid10583958">{{Cite journal
| last1 = Minegishi | first1 = Y.
| last2 = Rohrer | first2 = J.
| last3 = Coustan-Smith | first3 = E.
| last4 = Lederman | first4 = H. M.
| last5 = Pappu | first5 = R.
| last6 = Campana | first6 = D.  
| last7 = Chan | first7 = A. C.  
| last8 = Conley | first8 = M. E.  
| title = An essential role for BLNK in human B cell development
| journal = Science
| volume = 286
| issue = 5446
| pages = 1954–1957
| year = 1999
| pmid = 10583958 | doi=10.1126/science.286.5446.1954
}}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
{{PBB_Summary
| section_title =  
| section_title =  
| summary_text = Linker or adaptor proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. The B-cell linker protein is essential for normal B-cell development.[supplied by OMIM]<ref name="entrez">{{cite web | title = Entrez Gene: BLNK B-cell linker| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29760| accessdate = }}</ref>
| summary_text = Linker or adaptor proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. The B-cell linker protein is essential for normal B-cell development.[supplied by OMIM]<ref name="entrez"/>
}}
}}
==Structure==
BLNK consists of a N-terminal [[leucine zipper]] motif followed by an "acidic" region, a proline-rich region, and a C-terminal [[SH2 domain]]. The leucine zipper motif allows BLNK to localise to the plasma membrane, presumably by coiled-coil interactions with a membrane protein.<ref name="pmid15654340">{{Cite journal
| last1 = Köhler | first1 = F.
| last2 = Storch | first2 = B.
| last3 = Kulathu | first3 = Y.
| last4 = Herzog | first4 = S.
| last5 = Kuppig | first5 = S.
| last6 = Reth | first6 = M.
| last7 = Jumaa | first7 = H.
| doi = 10.1038/ni1163
| title = A leucine zipper in the N terminus confers membrane association to SLP-65
| journal = Nature Immunology
| volume = 6
| issue = 2
| pages = 204–210
| year = 2005
| pmid = 15654340
| pmc =
}}</ref> This leucine zipper motif distinguishes BLNK from its paralogue SLP-76 which, although having an N-terminal heptad-like organisation of leucine and isoleucine residues, has not been experimentally shown to have this motif. Recruitment of BLNK to the plasma membrane is also achieved by binding of the SH2 domain of BLNK to a non-[[immunoreceptor tyrosine-based activation motif|ITAM]] phospho-tyrosine on [[CD79A|Igα]], a part of the B cell receptor complex.<ref name="pmid11449366">{{Cite journal
| last1 = Engels | first1 = N.
| last2 = Wollscheid | first2 = B.
| last3 = Wienands | first3 = J. R.
| doi = 10.1002/1521-4141(200107)31:7<2126::AID-IMMU2126>3.0.CO;2-O
| title = Association of SLP-65 / BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-α
| journal = European Journal of Immunology
| volume = 31
| issue = 7
| pages = 2126–2134
| year = 2001
| pmid = 11449366
| pmc =
}}</ref><ref name="pmid11909947">{{Cite journal
| last1 = Kabak | first1 = S.
| last2 = Skaggs | first2 = B. J.
| last3 = Gold | first3 = M. R.
| last4 = Affolter | first4 = M.
| last5 = West | first5 = K. L.
| last6 = Foster | first6 = M. S.
| last7 = Siemasko | first7 = K.
| last8 = Chan | first8 = A. C.
| last9 = Aebersold | first9 = R.
| last10 = Clark | first10 = M. R.
| title = The Direct Recruitment of BLNK to Immunoglobulin α Couples the B-Cell Antigen Receptor to Distal Signaling Pathways
| journal = Molecular and Cellular Biology
| volume = 22
| issue = 8
| pages = 2524–2535
| year = 2002
| pmid = 11909947
| pmc = 133735 | doi=10.1128/MCB.22.8.2524-2535.2002
}}</ref><ref name="pmid15699130">{{Cite journal
| last1 = Pike | first1 = K. A.
| last2 = Ratcliffe | first2 = M. J.
| title = Dual requirement for the Ig alpha immunoreceptor tyrosine-based activation motif (ITAM) and a conserved non-Ig alpha ITAM tyrosine in supporting Ig alpha beta-mediated B cell development
| journal = Journal of Immunology
| volume = 174
| issue = 4
| pages = 2012–2020
| year = 2005
| pmid = 15699130
| doi=10.4049/jimmunol.174.4.2012
}}</ref>
The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five in humans, that mediate protein-protein interactions between BLNK and [[PLCG2|PLCγ2]], [[Bruton's tyrosine kinase|Btk]], [[Vav (protein)|Vav]], and [[Nck1|Nck]].<ref name="pmid12456653">{{Cite journal
| last1 = Chiu | first1 = C. W.
| last2 = Dalton | first2 = M.
| last3 = Ishiai | first3 = M.
| last4 = Kurosaki | first4 = T.
| last5 = Chan | first5 = A. C.
| title = BLNK: Molecular scaffolding through 'cis'-mediated organization of signaling proteins
| journal = The EMBO Journal
| volume = 21
| issue = 23
| pages = 6461–6472
| year = 2002
| pmid = 12456653
| pmc = 136961 | doi=10.1093/emboj/cdf658
}}</ref> A more recent mass spectrometry study of BLNK in DT40 cells found that at least 41 unique serine, threonine, and tyrosine residues are phosphorylated on BLNK.<ref name="pmid19372136">{{Cite journal
| last1 = Oellerich | first1 = T.
| last2 = Gronborg | first2 = M.
| last3 = Neumann | first3 = K.
| last4 = Hsiao | first4 = H. -H.
| last5 = Urlaub | first5 = H.
| last6 = Wienands | first6 = J.
| title = SLP-65 Phosphorylation Dynamics Reveals a Functional Basis for Signal Integration by Receptor-proximal Adaptor Proteins
| doi = 10.1074/mcp.M800567-MCP200
| journal = Molecular & Cellular Proteomics
| volume = 8
| issue = 7
| pages = 1738–1750
| pmc = 2709198
| year = 2009
| pmid = 19372136
}}</ref>
==Interactions==
B-cell linker has been shown to [[Protein-protein interaction|interact]] with [[Grb2]],<ref name="pmid9697839" /><ref name="pmid9705962" /><ref name="pmid11449366" /><ref name="pmid10820378">{{Cite journal
| last1 = Fusaki | first1 = N.
| last2 = Tomita | first2 = S.
| last3 = Wu | first3 = Y.
| last4 = Okamoto | first4 = N.
| last5 = Goitsuka | first5 = R.
| last6 = Kitamura | first6 = D.
| last7 = Hozumi | first7 = N.
| doi = 10.1002/(SICI)1521-4141(200005)30:5<1326::AID-IMMU1326>3.0.CO;2-Q
| title = BLNK is associated with the CD72 / SHP-1 / Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking
| journal = European Journal of Immunology
| volume = 30
| issue = 5
| pages = 1326–1330
| year = 2000
| pmid = 10820378
}}</ref> [[SH3KBP1]],<ref name="pmid11071869">{{Cite journal
| last1 = Watanabe | first1 = S.
| last2 = Take | first2 = H.
| last3 = Takeda | first3 = K.
| last4 = Yu | first4 = Z. X.
| last5 = Iwata | first5 = N.
| last6 = Kajigaya | first6 = S.
| doi = 10.1006/bbrc.2000.3760
| title = Characterization of the CIN85 Adaptor Protein and Identification of Components Involved in CIN85 Complexes
| journal = Biochemical and Biophysical Research Communications
| volume = 278
| issue = 1
| pages = 167–174
| year = 2000
| pmid = 11071869
}}</ref> [[CD79A]],<ref name="pmid11449366" /><ref name="pmid11909947" /> [[MAP4K1]]<ref name="pmid11514608">{{Cite journal
| last1 = Tsuji | first1 = S.
| last2 = Okamoto | first2 = M.
| last3 = Yamada | first3 = K.
| last4 = Okamoto | first4 = N.
| last5 = Goitsuka | first5 = R.
| last6 = Arnold | first6 = R.
| last7 = Kiefer | first7 = F.
| last8 = Kitamura | first8 = D.
| title = B Cell Adaptor Containing Src Homology 2 Domain (Bash) Links B Cell Receptor Signaling to the Activation of Hematopoietic Progenitor Kinase 1
| journal = The Journal of Experimental Medicine
| volume = 194
| issue = 4
| pages = 529–539
| year = 2001
| pmid = 11514608
| pmc = 2193495 | doi=10.1084/jem.194.4.529
}}</ref> and [[Bruton's tyrosine kinase]].<ref name="pmid12093870">{{Cite journal
| last1 = Yasuda | first1 = T.
| last2 = Tezuka | first2 = T.
| last3 = Maeda | first3 = A.
| last4 = Inazu | first4 = T.
| last5 = Yamanashi | first5 = Y.
| last6 = Gu | first6 = H.
| last7 = Kurosaki | first7 = T.
| last8 = Yamamoto | first8 = T.
| title = Cbl-b Positively Regulates Btk-mediated Activation of Phospholipase C-γ2 in B Cells
| journal = The Journal of Experimental Medicine
| volume = 196
| issue = 1
| pages = 51–63
| year = 2002
| pmid = 12093870
| pmc = 2194016 | doi=10.1084/jem.20020068
}}</ref><ref name=pmid10498607>{{Cite journal
| last1 = Hashimoto | first1 = S.
| last2 = Iwamatsu | first2 = A.
| last3 = Ishiai | first3 = M.
| last4 = Okawa | first4 = K.
| last5 = Yamadori | first5 = T.
| last6 = Matsushita | first6 = M.
| last7 = Baba | first7 = Y.
| last8 = Kishimoto | first8 = T.
| last9 = Kurosaki | first9 = T.
| last10 = Tsukada | first10 = S.
| title = Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK--functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling
| journal = Blood
| volume = 94
| issue = 7
| pages = 2357–2364
| year = 1999
| pmid = 10498607
}}</ref>
==Post-translational modification==
{{Empty section|date=September 2012}}


==References==
==References==
{{reflist|2}}
{{reflist}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading  
{{PBB_Further_reading  
| citations =  
| citations =  
*{{cite journal  | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi=  }}
*{{cite journal  | vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides |journal=Gene |volume=138 |issue= 1–2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8 }}
*{{cite journal  | author=Fu C, Chan AC |title=Identification of two tyrosine phosphoproteins, pp70 and pp68, which interact with phospholipase Cgamma, Grb2, and Vav after B cell antigen receptor activation. |journal=J. Biol. Chem. |volume=272 |issue= 43 |pages= 27362-8 |year= 1997 |pmid= 9341187 |doi= }}
*{{cite journal  | vauthors=Fu C, Chan AC |title=Identification of two tyrosine phosphoproteins, pp70 and pp68, which interact with phospholipase Cgamma, Grb2, and Vav after B cell antigen receptor activation |journal=J. Biol. Chem. |volume=272 |issue= 43 |pages= 27362–8 |year= 1997 |pmid= 9341187 |doi=10.1074/jbc.272.43.27362  }}
*{{cite journal  | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi=  }}
*{{cite journal  | author=Suzuki Y |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library |journal=Gene |volume=200 |issue= 1–2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=10.1016/S0378-1119(97)00411-3 |name-list-format=vanc| author2=Yoshitomo-Nakagawa K | author3=Maruyama K  | display-authors=3  | last4=Suyama  | first4=A  | last5=Sugano  | first5=S }}
*{{cite journal | author=Fu C, Turck CW, Kurosaki T, Chan AC |title=BLNK: a central linker protein in B cell activation. |journal=Immunity |volume=9 |issue= 1 |pages= 93-103 |year= 1998 |pmid= 9697839 |doi=  }}
*{{cite journal  | author=Wienands J |title=SLP-65: a new signaling component in B lymphocytes that requires expression of the antigen receptor for phosphorylation |journal=J. Exp. Med. |volume=188 |issue= 4 |pages= 791–5 |year= 1998 |pmid= 9705962 |doi=10.1084/jem.188.4.791 | pmc=2213353 |name-list-format=vanc| author2=Schweikert J  | author3=Wollscheid B | display-authors=3  | last4=Jumaa  | first4=H  | last5=Nielsen  | first5=PJ  | last6=Reth  | first6=M }}
*{{cite journal  | author=Wienands J, Schweikert J, Wollscheid B, ''et al.'' |title=SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation. |journal=J. Exp. Med. |volume=188 |issue= 4 |pages= 791-5 |year= 1998 |pmid= 9705962 |doi=  }}
*{{cite journal  | author=Hashimoto S |title=Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK--functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling |journal=Blood |volume=94 |issue= 7 |pages= 2357–64 |year= 1999 |pmid= 10498607  |name-list-format=vanc| author2=Iwamatsu A | author3=Ishiai M  | display-authors=3 | last4=Okawa  | first4=K  | last5=Yamadori  | first5=T  | last6=Matsushita  | first6=M  | last7=Baba  | first7=Y  | last8=Kishimoto | first8=T  | last9=Kurosaki  | first9=T }}
*{{cite journal | author=Hashimoto S, Iwamatsu A, Ishiai M, ''et al.'' |title=Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK--functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling. |journal=Blood |volume=94 |issue= 7 |pages= 2357-64 |year= 1999 |pmid= 10498607 |doi=  }}
*{{cite journal  | author=Su YW |title=Interaction of SLP adaptors with the SH2 domain of Tec family kinases |journal=Eur. J. Immunol. |volume=29 |issue= 11 |pages= 3702–11 |year= 1999 |pmid= 10556826 |doi=10.1002/(SICI)1521-4141(199911)29:11<3702::AID-IMMU3702>3.0.CO;2-R |name-list-format=vanc| author2=Zhang Y | author3=Schweikert J  | display-authors=3  | last4=Koretzky  | first4=Gary A.  | last5=Reth  | first5=Michael  | last6=Wienands  | first6=Jürgen }}
*{{cite journal  | author=Su YW, Zhang Y, Schweikert J, ''et al.'' |title=Interaction of SLP adaptors with the SH2 domain of Tec family kinases. |journal=Eur. J. Immunol. |volume=29 |issue= 11 |pages= 3702-11 |year= 1999 |pmid= 10556826 |doi=  }}
*{{cite journal  | author=Fusaki N |title=BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking |journal=Eur. J. Immunol. |volume=30 |issue= 5 |pages= 1326–30 |year= 2000 |pmid= 10820378 |doi=10.1002/(SICI)1521-4141(200005)30:5<1326::AID-IMMU1326>3.0.CO;2-Q |name-list-format=vanc| author2=Tomita S | author3=Wu Y  | display-authors=3  | last4=Okamoto  | first4=Noriaki  | last5=Goitsuka  | first5=Ryo  | last6=Kitamura  | first6=Daisuke  | last7=Hozumi  | first7=Nobumichi  }}
*{{cite journal | author=Minegishi Y, Rohrer J, Coustan-Smith E, ''et al.'' |title=An essential role for BLNK in human B cell development. |journal=Science |volume=286 |issue= 5446 |pages= 1954-7 |year= 1999 |pmid= 10583958 |doi=  }}
*{{cite journal  | author=Mizuno K |title=Src homology region 2 (SH2) domain-containing phosphatase-1 dephosphorylates B cell linker protein/SH2 domain leukocyte protein of 65 kDa and selectively regulates c-Jun NH2-terminal kinase activation in B cells |journal=J. Immunol. |volume=165 |issue= 3 |pages= 1344–51 |year= 2000 |pmid= 10903736 |doi= 10.4049/jimmunol.165.3.1344|name-list-format=vanc| author2=Tagawa Y | author3=Mitomo K  | display-authors=3  | last4=Arimura  | first4=Y  | last5=Hatano  | first5=N  | last6=Katagiri  | first6=T  | last7=Ogimoto  | first7=M  | last8=Yakura  | first8=H  }}
*{{cite journal  | author=Fusaki N, Tomita S, Wu Y, ''et al.'' |title=BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking. |journal=Eur. J. Immunol. |volume=30 |issue= 5 |pages= 1326-30 |year= 2000 |pmid= 10820378 |doi= }}
*{{cite journal  | author=Guo B |title=Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex |journal=Immunity |volume=13 |issue= 2 |pages= 243–53 |year= 2000 |pmid= 10981967 |doi=10.1016/S1074-7613(00)00024-8 |name-list-format=vanc| author2=Kato RM  | author3=Garcia-Lloret M  | display-authors=3  | last4=Wahl  | first4=Matthew I  | last5=Rawlings  | first5=David J  }}
*{{cite journal | author=Mizuno K, Tagawa Y, Mitomo K, ''et al.'' |title=Src homology region 2 (SH2) domain-containing phosphatase-1 dephosphorylates B cell linker protein/SH2 domain leukocyte protein of 65 kDa and selectively regulates c-Jun NH2-terminal kinase activation in B cells. |journal=J. Immunol. |volume=165 |issue= 3 |pages= 1344-51 |year= 2000 |pmid= 10903736 |doi=  }}
*{{cite journal  | author=Watanabe S |title=Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes |journal=Biochem. Biophys. Res. Commun. |volume=278 |issue= 1 |pages= 167–74 |year= 2001 |pmid= 11071869 |doi= 10.1006/bbrc.2000.3760 |name-list-format=vanc| author2=Take H  | author3=Takeda K | display-authors=3  | last4=Yu  | first4=ZX  | last5=Iwata  | first5=N  | last6=Kajigaya  | first6=S }}
*{{cite journal  | author=Guo B, Kato RM, Garcia-Lloret M, ''et al.'' |title=Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex. |journal=Immunity |volume=13 |issue= 2 |pages= 243-53 |year= 2000 |pmid= 10981967 |doi=  }}
*{{cite journal  | author=Tan JE |title=The adaptor protein BLNK is required for b cell antigen receptor-induced activation of nuclear factor-kappa B and cell cycle entry and survival of B lymphocytes |journal=J. Biol. Chem. |volume=276 |issue= 23 |pages= 20055–63 |year= 2001 |pmid= 11274146 |doi= 10.1074/jbc.M010800200 |name-list-format=vanc| author2=Wong SC  | author3=Gan SK  | display-authors=3  | last4=Xu  | first4=S  | last5=Lam  | first5=KP }}
*{{cite journal  | author=Watanabe S, Take H, Takeda K, ''et al.'' |title=Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes. |journal=Biochem. Biophys. Res. Commun. |volume=278 |issue= 1 |pages= 167-74 |year= 2001 |pmid= 11071869 |doi= 10.1006/bbrc.2000.3760 }}
*{{cite journal | author=Adachi T |title=SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates |journal=J. Biol. Chem. |volume=276 |issue= 28 |pages= 26648–55 |year= 2001 |pmid= 11356834 |doi= 10.1074/jbc.M100997200  |name-list-format=vanc| author2=Wienands J  | author3=Wakabayashi C  | display-authors=3  | last4=Yakura  | first4=H  | last5=Reth  | first5=M  | last6=Tsubata  | first6=T }}
*{{cite journal  | author=Tan JE, Wong SC, Gan SK, ''et al.'' |title=The adaptor protein BLNK is required for b cell antigen receptor-induced activation of nuclear factor-kappa B and cell cycle entry and survival of B lymphocytes. |journal=J. Biol. Chem. |volume=276 |issue= 23 |pages= 20055-63 |year= 2001 |pmid= 11274146 |doi= 10.1074/jbc.M010800200 }}
*{{cite journal  | vauthors=Engels N, Wollscheid B, Wienands J |title=Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha |journal=Eur. J. Immunol. |volume=31 |issue= 7 |pages= 2126–34 |year= 2001 |pmid= 11449366 |doi=10.1002/1521-4141(200107)31:7<2126::AID-IMMU2126>3.0.CO;2-O  }}
*{{cite journal | author=Adachi T, Wienands J, Wakabayashi C, ''et al.'' |title=SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates. |journal=J. Biol. Chem. |volume=276 |issue= 28 |pages= 26648-55 |year= 2001 |pmid= 11356834 |doi= 10.1074/jbc.M100997200 }}
*{{cite journal  | author=Sauer K |title=Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes |journal=J. Biol. Chem. |volume=276 |issue= 48 |pages= 45207–16 |year= 2002 |pmid= 11487585 |doi= 10.1074/jbc.M106811200  |name-list-format=vanc| author2=Liou J  | author3=Singh SB  | display-authors=3  | last4=Yablonski  | first4=D  | last5=Weiss  | first5=A  | last6=Perlmutter  | first6=RM }}
*{{cite journal  | author=Engels N, Wollscheid B, Wienands J |title=Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha. |journal=Eur. J. Immunol. |volume=31 |issue= 7 |pages= 2126-34 |year= 2001 |pmid= 11449366 |doi= }}
*{{cite journal  | author=Engels N |title=Epstein-Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module |journal=J. Exp. Med. |volume=194 |issue= 3 |pages= 255–64 |year= 2001 |pmid= 11489945 |doi=10.1084/jem.194.3.255  | pmc=2193464  |name-list-format=vanc| author2=Merchant M  | author3=Pappu R  | display-authors=3  | last4=Chan  | first4=A. C.  | last5=Longnecker  | first5=R.  | last6=Wienands  | first6=J.  }}
*{{cite journal | author=Sauer K, Liou J, Singh SB, ''et al.'' |title=Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes. |journal=J. Biol. Chem. |volume=276 |issue= 48 |pages= 45207-16 |year= 2002 |pmid= 11487585 |doi= 10.1074/jbc.M106811200 }}
*{{cite journal  | author=Tsuji S |title=B cell adaptor containing src homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1 |journal=J. Exp. Med. |volume=194 |issue= 4 |pages= 529–39 |year= 2001 |pmid= 11514608 |doi=10.1084/jem.194.4.529  | pmc=2193495  |name-list-format=vanc| author2=Okamoto M  | author3=Yamada K  | display-authors=3  | last4=Okamoto  | first4=N.  | last5=Goitsuka  | first5=R.  | last6=Arnold  | first6=R.  | last7=Kiefer  | first7=F.  | last8=Kitamura  | first8=D.  }}
*{{cite journal  | author=Engels N, Merchant M, Pappu R, ''et al.'' |title=Epstein-Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module. |journal=J. Exp. Med. |volume=194 |issue= 3 |pages= 255-64 |year= 2001 |pmid= 11489945 |doi=  }}
*{{cite journal  | author=Kabak S |title=The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways |journal=Mol. Cell. Biol. |volume=22 |issue= 8 |pages= 2524–35 |year= 2002 |pmid= 11909947 |doi=10.1128/MCB.22.8.2524-2535.2002  | pmc=133735  |name-list-format=vanc| author2=Skaggs BJ  | author3=Gold MR  | display-authors=3  | last4=Affolter  | first4=M.  | last5=West  | first5=K. L.  | last6=Foster  | first6=M. S.  | last7=Siemasko  | first7=K.  | last8=Chan  | first8=A. C.  | last9=Aebersold  | first9=R.  }}
*{{cite journal  | author=Tsuji S, Okamoto M, Yamada K, ''et al.'' |title=B cell adaptor containing src homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1. |journal=J. Exp. Med. |volume=194 |issue= 4 |pages= 529-39 |year= 2001 |pmid= 11514608 |doi=  }}
*{{cite journal  | author=Yasuda T |title=Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells |journal=J. Exp. Med. |volume=196 |issue= 1 |pages= 51–63 |year= 2002 |pmid= 12093870 |doi=10.1084/jem.20020068  | pmc=2194016  |name-list-format=vanc| author2=Tezuka T  | author3=Maeda A  | display-authors=3  | last4=Inazu  | first4=T.  | last5=Yamanashi  | first5=Y.  | last6=Gu  | first6=H.  | last7=Kurosaki  | first7=T.  | last8=Yamamoto  | first8=T.  }}
*{{cite journal  | author=Kabak S, Skaggs BJ, Gold MR, ''et al.'' |title=The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways. |journal=Mol. Cell. Biol. |volume=22 |issue= 8 |pages= 2524-35 |year= 2002 |pmid= 11909947 |doi= }}
*{{cite journal | author=Yasuda T, Tezuka T, Maeda A, ''et al.'' |title=Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells. |journal=J. Exp. Med. |volume=196 |issue= 1 |pages= 51-63 |year= 2002 |pmid= 12093870 |doi= }}
}}
}}
{{refend}}
{{refend}}


{{protein-stub}}
==External links==
{{WikiDoc Sources}}
* {{UCSC gene info|BLNK}}
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[[Category:Proteins]]

Revision as of 02:20, 30 August 2017

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Identifiers
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Orthologs
SpeciesHumanMouse
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The B-cell linker protein is encoded by the BLNK gene[1][2] and is an adaptor protein also known as SLP-65,[3] BASH,[4] and BCA.[5] BLNK is expressed in B cells and macrophages and plays a large role in B cell receptor signalling, in a fashion analogous to the role its paralogue SLP-76 plays in T cell receptor signalling.[6] As it has no known intrinsic enzymatic activity, the function of BLNK is to temporally and spatially coordinate and regulate signalling effectors downstream of the B cell receptor.

Function

The function of BLNK was first illustrated in BLNK deficient DT40 cells, a chicken B-cell line, which exhibited an abrogated intracellular calcium mobilisation response and impaired activation of MAP kinases p38, JNK, and to a lesser degree ERK upon B-cell receptor (BCR) activation as compared to wild type DT40 cells.[7] In knockout mice, BLNK deficiency results in a partial block in B-cell development,[8][9] and in humans BLNK deficiency results in a much more profound block in B-cell development.[10]

Linker or adaptor proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. The B-cell linker protein is essential for normal B-cell development.[supplied by OMIM][2]

Structure

BLNK consists of a N-terminal leucine zipper motif followed by an "acidic" region, a proline-rich region, and a C-terminal SH2 domain. The leucine zipper motif allows BLNK to localise to the plasma membrane, presumably by coiled-coil interactions with a membrane protein.[11] This leucine zipper motif distinguishes BLNK from its paralogue SLP-76 which, although having an N-terminal heptad-like organisation of leucine and isoleucine residues, has not been experimentally shown to have this motif. Recruitment of BLNK to the plasma membrane is also achieved by binding of the SH2 domain of BLNK to a non-ITAM phospho-tyrosine on Igα, a part of the B cell receptor complex.[12][13][14]

The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five in humans, that mediate protein-protein interactions between BLNK and PLCγ2, Btk, Vav, and Nck.[15] A more recent mass spectrometry study of BLNK in DT40 cells found that at least 41 unique serine, threonine, and tyrosine residues are phosphorylated on BLNK.[16]

Interactions

B-cell linker has been shown to interact with Grb2,[1][3][12][17] SH3KBP1,[18] CD79A,[12][13] MAP4K1[19] and Bruton's tyrosine kinase.[20][21]

Post-translational modification

References

  1. ↑ 1.0 1.1 Fu, C.; Turck, C. W.; Kurosaki, T.; Chan, A. C. (1998). "BLNK: A central linker protein in B cell activation". Immunity. 9 (1): 93–103. doi:10.1016/S1074-7613(00)80591-9. PMID 9697839.
  2. ↑ 2.0 2.1 "Entrez Gene: BLNK B-cell linker".
  3. ↑ 3.0 3.1 Wienands, J.; Schweikert, J.; Wollscheid, B.; Jumaa, H.; Nielsen, P. J.; Reth, M. (1998). "SLP-65: A new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation". The Journal of Experimental Medicine. 188 (4): 791–795. doi:10.1084/jem.188.4.791. PMC 2213353. PMID 9705962.
  4. ↑ Goitsuka, R.; Fujimura, Y.; Mamada, H.; Umeda, A.; Morimura, T.; Uetsuka, K.; Doi, K.; Tsuji, S.; Kitamura, D. (1998). "BASH, a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius". Journal of Immunology. 161 (11): 5804–5808. PMID 9834055.
  5. ↑ Gangi-Peterson, L.; Peterson, S. N.; Shapiro, L. H.; Golding, A.; Caricchio, R.; Cohen, D. I.; Margulies, D. H.; Cohen, P. L. (1998). "Bca: An activation-related B-cell gene". Molecular immunology. 35 (1): 55–63. doi:10.1016/s0161-5890(98)00008-x. PMID 9683264.
  6. ↑ Koretzky, G. A.; Abtahian, F.; Silverman, M. A. (2006). "SLP76 and SLP65: Complex regulation of signalling in lymphocytes and beyond". Nature Reviews Immunology. 6 (1): 67–78. doi:10.1038/nri1750. PMID 16493428.
  7. ↑ Ishiai, M.; Kurosaki, M.; Pappu, R.; Okawa, K.; Ronko, I.; Fu, C.; Shibata, M.; Iwamatsu, A.; Chan, A. C.; Kurosaki, T. (1999). "BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells". Immunity. 10 (1): 117–125. doi:10.1016/S1074-7613(00)80012-6. PMID 10023776.
  8. ↑ Jumaa, H.; Wollscheid, B.; Mitterer, M.; Wienands, J.; Reth, M.; Nielsen, P. J. (1999). "Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65". Immunity. 11 (5): 547–554. doi:10.1016/S1074-7613(00)80130-2. PMID 10591180.
  9. ↑ Pappu, R.; Cheng, A. M.; Li, B.; Gong, Q.; Chiu, C.; Griffin, N.; White, M.; Sleckman, B. P.; Chan, A. C. (1999). "Requirement for B cell linker protein (BLNK) in B cell development". Science. 286 (5446): 1949–1954. doi:10.1126/science.286.5446.1949. PMID 10583957.
  10. ↑ Minegishi, Y.; Rohrer, J.; Coustan-Smith, E.; Lederman, H. M.; Pappu, R.; Campana, D.; Chan, A. C.; Conley, M. E. (1999). "An essential role for BLNK in human B cell development". Science. 286 (5446): 1954–1957. doi:10.1126/science.286.5446.1954. PMID 10583958.
  11. ↑ Köhler, F.; Storch, B.; Kulathu, Y.; Herzog, S.; Kuppig, S.; Reth, M.; Jumaa, H. (2005). "A leucine zipper in the N terminus confers membrane association to SLP-65". Nature Immunology. 6 (2): 204–210. doi:10.1038/ni1163. PMID 15654340.
  12. ↑ 12.0 12.1 12.2 Engels, N.; Wollscheid, B.; Wienands, J. R. (2001). "Association of SLP-65 / BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-α". European Journal of Immunology. 31 (7): 2126–2134. doi:10.1002/1521-4141(200107)31:7<2126::AID-IMMU2126>3.0.CO;2-O. PMID 11449366.
  13. ↑ 13.0 13.1 Kabak, S.; Skaggs, B. J.; Gold, M. R.; Affolter, M.; West, K. L.; Foster, M. S.; Siemasko, K.; Chan, A. C.; Aebersold, R.; Clark, M. R. (2002). "The Direct Recruitment of BLNK to Immunoglobulin α Couples the B-Cell Antigen Receptor to Distal Signaling Pathways". Molecular and Cellular Biology. 22 (8): 2524–2535. doi:10.1128/MCB.22.8.2524-2535.2002. PMC 133735. PMID 11909947.
  14. ↑ Pike, K. A.; Ratcliffe, M. J. (2005). "Dual requirement for the Ig alpha immunoreceptor tyrosine-based activation motif (ITAM) and a conserved non-Ig alpha ITAM tyrosine in supporting Ig alpha beta-mediated B cell development". Journal of Immunology. 174 (4): 2012–2020. doi:10.4049/jimmunol.174.4.2012. PMID 15699130.
  15. ↑ Chiu, C. W.; Dalton, M.; Ishiai, M.; Kurosaki, T.; Chan, A. C. (2002). "BLNK: Molecular scaffolding through 'cis'-mediated organization of signaling proteins". The EMBO Journal. 21 (23): 6461–6472. doi:10.1093/emboj/cdf658. PMC 136961. PMID 12456653.
  16. ↑ Oellerich, T.; Gronborg, M.; Neumann, K.; Hsiao, H. -H.; Urlaub, H.; Wienands, J. (2009). "SLP-65 Phosphorylation Dynamics Reveals a Functional Basis for Signal Integration by Receptor-proximal Adaptor Proteins". Molecular & Cellular Proteomics. 8 (7): 1738–1750. doi:10.1074/mcp.M800567-MCP200. PMC 2709198. PMID 19372136.
  17. ↑ Fusaki, N.; Tomita, S.; Wu, Y.; Okamoto, N.; Goitsuka, R.; Kitamura, D.; Hozumi, N. (2000). "BLNK is associated with the CD72 / SHP-1 / Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking". European Journal of Immunology. 30 (5): 1326–1330. doi:10.1002/(SICI)1521-4141(200005)30:5<1326::AID-IMMU1326>3.0.CO;2-Q. PMID 10820378.
  18. ↑ Watanabe, S.; Take, H.; Takeda, K.; Yu, Z. X.; Iwata, N.; Kajigaya, S. (2000). "Characterization of the CIN85 Adaptor Protein and Identification of Components Involved in CIN85 Complexes". Biochemical and Biophysical Research Communications. 278 (1): 167–174. doi:10.1006/bbrc.2000.3760. PMID 11071869.
  19. ↑ Tsuji, S.; Okamoto, M.; Yamada, K.; Okamoto, N.; Goitsuka, R.; Arnold, R.; Kiefer, F.; Kitamura, D. (2001). "B Cell Adaptor Containing Src Homology 2 Domain (Bash) Links B Cell Receptor Signaling to the Activation of Hematopoietic Progenitor Kinase 1". The Journal of Experimental Medicine. 194 (4): 529–539. doi:10.1084/jem.194.4.529. PMC 2193495. PMID 11514608.
  20. ↑ Yasuda, T.; Tezuka, T.; Maeda, A.; Inazu, T.; Yamanashi, Y.; Gu, H.; Kurosaki, T.; Yamamoto, T. (2002). "Cbl-b Positively Regulates Btk-mediated Activation of Phospholipase C-γ2 in B Cells". The Journal of Experimental Medicine. 196 (1): 51–63. doi:10.1084/jem.20020068. PMC 2194016. PMID 12093870.
  21. ↑ Hashimoto, S.; Iwamatsu, A.; Ishiai, M.; Okawa, K.; Yamadori, T.; Matsushita, M.; Baba, Y.; Kishimoto, T.; Kurosaki, T.; Tsukada, S. (1999). "Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK--functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling". Blood. 94 (7): 2357–2364. PMID 10498607.

Further reading

External links

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