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B-cell linker

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BLNK
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesBLNK,AGM4, BASH, BLNK-S, LY57, SLP-65, SLP65, bca, B-cell linker, B cell linker
External IDsOMIM:604515;MGI:96878;HomoloGene:32038;GeneCards:BLNK;OMA:BLNK - orthologs
Orthologs
SpeciesHumanMouse
Entrez

29760

17060

Ensembl

ENSG00000095585

ENSMUSG00000061132

UniProt

Q8WV28

Q9QUN3

RefSeq (mRNA)

NM_001114094
NM_001258440
NM_001258441
NM_001258442
NM_013314

NM_008528
NM_001365054

RefSeq (protein)

NP_001107566
NP_001245369
NP_001245370
NP_001245371
NP_037446

NP_032554
NP_001351983

Location (UCSC)Chr 10: 96.19 – 96.27 MbChr 19: 40.92 – 40.98 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

B-cell linker (BLNK)protein is expressed inB cellsandmacrophagesand plays a large role inB cell receptorsignaling.[5]Like alladaptor proteins,BLNK has no known intrinsic enzymatic activity.[6]Its function is to temporally and spatially coordinate and regulatedownstreamsignaling effectors inB cell receptor(BCR) signaling, which is important in B cell development.[7]Binding of these downstream effectors is dependent on BLNK phosphorylation.[8][9]BLNK is encoded by theBLNKgene[8][10]and is also known asSLP-65,[11]BASH,[12]andBCA.[13]

Structure and localization

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BLNK consists of a N-terminalleucine zippermotif followed by an acidic region, a proline-rich region, and a C-terminalSH2 domain.[14][5]The leucine zipper motif allows BLNK to localize to the plasma membrane, presumably by coiled-coil interactions with a membrane protein.[5]This leucine zipper motif distinguishes BLNK fromlymphoctye cytosolic protein 2,also known as LCP-2 or SLP-76, which plays a similar role inT cell receptorsignaling.[15]Although LCP-2 has an N-terminal heptad-like organization of leucine and isoleucine residues like BLNK, it has not been experimentally shown to have the leucine zipper motif.[16]Recruitment of BLNK to the plasma membrane is also achieved by binding of the SH2 domain of BLNK to a non-ITAMphospho-tyrosine on the cytoplasmic domain ofCD79A,which is a part ofIgαand the B cell receptor complex.[17][18][19]

Function

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BLNK’s function and interaction shown in a schematic of BCR signaling pathways. BCR antigen recognition activatesSrc family kinases,including theSYKandBTKtyrosine kinases.Syk then phosphorylates BLNK, which can recruit downstream signaling molecules such asGrb2,PLCG2,VavandNck.

BLNK's function and importance in B cell development were first illustrated in BLNK deficient DT40 cells, achickenB cellline.[7]DT40 cells had interrupted B cell development: there was no calcium mobilization response in the B cell, impaired activation of themitogen-activated protein (MAP) kinasesp38,JNK,and somewhat inhibitedERKactivation upon (BCR) activation as compared to wild type DT40 cells.[7]Inknockout mice,BLNK deficiency results in a partial block in B cell development,[20][21]and in humans BLNK deficiency results in a much more profound block in B cell development.[22][5]

Linker or adaptor proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins.[6]BLNK is essential for normal B-cell development as part of the B cell receptor signaling pathway. [supplied by OMIM][10][23][24]

Evidence also suggests that BLNK may have tumor suppressive activity through its interaction withBruton's tyrosine kinase(Btk)[25][26]and regulation of the pre-B cell checkpoint.[14][27]

Phosphorylation and interactions

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The acidic region of BLNK contains several inducibly phosphorylatedtyrosineresidues, at least five of which are found in humans.[28]Evidence suggests that BLNK is phosphorylated by thetyrosine-protein kinase Sykafter B cell receptor activation.[8][9][24][29]Phosphorylation of these residues provides docking sites necessary for downstreamprotein-protein interactionsbetween BLNK and the SH2 domain-containing proteinsGrb2,[8][11][17][30]PLCG2,Btk,theVavprotein family, andNck.[31][9][8]BLNK has also been shown to interact withSH3KBP1[32]andMAP4K1.[33]A more recentmass spectrometrystudy of BLNK in DT40 cells found that at least 41 unique serine, threonine, and tyrosine residues are phosphorylated on BLNK.[34]

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000095585–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000061132–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abcdKöhler F, Storch B, Kulathu Y, Herzog S, Kuppig S, Reth M, Jumaa H (February 2005). "A leucine zipper in the N terminus confers membrane association to SLP-65".Nature Immunology.6(2): 204–210.doi:10.1038/ni1163.PMID15654340.S2CID10708737.
  6. ^abBorowicz P, Chan H, Hauge A, Spurkland A (November 2020). "Adaptor proteins: Flexible and dynamic modulators of immune cell signalling".Scandinavian Journal of Immunology.92(5): e12951.doi:10.1111/sji.12951.hdl:10852/82328.PMID32734639.S2CID220892370.
  7. ^abcIshiai M, Kurosaki M, Pappu R, Okawa K, Ronko I, Fu C, et al. (January 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.PMID10023776.
  8. ^abcdeFu C, Turck CW, Kurosaki T, Chan AC (July 1998)."BLNK: a central linker protein in B cell activation".Immunity.9(1): 93–103.doi:10.1016/S1074-7613(00)80591-9.PMID9697839.
  9. ^abcHong JJ, Yankee TM, Harrison ML, Geahlen RL (August 2002)."Regulation of signaling in B cells through the phosphorylation of Syk on linker region tyrosines. A mechanism for negative signaling by the Lyn tyrosine kinase".The Journal of Biological Chemistry.277(35): 31703–31714.doi:10.1074/jbc.M201362200.PMID12077122.
  10. ^ab"Entrez Gene: BLNK B-cell linker".
  11. ^abWienands J, Schweikert J, Wollscheid B, Jumaa H, Nielsen PJ, Reth M (August 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.PMC2213353.PMID9705962.
  12. ^Goitsuka R, Fujimura Y, Mamada H, Umeda A, Morimura T, Uetsuka K, et al. (December 1998)."BASH, a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius".Journal of Immunology.161(11): 5804–5808.doi:10.4049/jimmunol.161.11.5804.PMID9834055.S2CID38459642.
  13. ^Gangi-Peterson L, Peterson SN, Shapiro LH, Golding A, Caricchio R, Cohen DI, et al. (January 1998). "bca: an activation-related B-cell gene".Molecular Immunology.35(1): 55–63.doi:10.1016/s0161-5890(98)00008-x.PMID9683264.
  14. ^abHerzog S, Storch B, Jumaa H (2006). "Dual role of the adaptor protein SLP-65: organizer of signal transduction and tumor suppressor of pre-B cell leukemia".Immunologic Research.34(2): 143–155.doi:10.1385/ir:34:2:143.PMID16760574.S2CID11515343.
  15. ^Koretzky GA, Abtahian F, Silverman MA (January 2006). "SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond".Nature Reviews. Immunology.6(1): 67–78.doi:10.1038/nri1750.PMID16493428.S2CID22368341.
  16. ^Rudd CE, Raab M (April 2003). "Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation".Immunological Reviews.192(1): 32–41.doi:10.1034/j.1600-065X.2003.00005.x.PMID12670393.S2CID33990866.
  17. ^abEngels N, Wollscheid B, Wienands J (July 2001). "Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha".European Journal of Immunology.31(7): 2126–2134.doi:10.1002/1521-4141(200107)31:7<2126::AID-IMMU2126>3.0.CO;2-O.PMID11449366.S2CID31494726.
  18. ^Kabak S, Skaggs BJ, Gold MR, Affolter M, West KL, Foster MS, et al. (April 2002)."The direct recruitment of BLNK to immunoglobulin alpha 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.PMC133735.PMID11909947.
  19. ^Pike KA, Ratcliffe MJ (February 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.PMID15699130.
  20. ^Jumaa H, Wollscheid B, Mitterer M, Wienands J, Reth M, Nielsen PJ (November 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.PMID10591180.
  21. ^Pappu R, Cheng AM, Li B, Gong Q, Chiu C, Griffin N, et al. (December 1999). "Requirement for B cell linker protein (BLNK) in B cell development".Science.286(5446): 1949–1954.doi:10.1126/science.286.5446.1949.PMID10583957.
  22. ^Minegishi Y, Rohrer J, Coustan-Smith E, Lederman HM, Pappu R, Campana D, et al. (December 1999). "An essential role for BLNK in human B cell development".Science.286(5446): 1954–1957.doi:10.1126/science.286.5446.1954.PMID10583958.
  23. ^Wang LD, Clark MR (December 2003)."B-cell antigen-receptor signalling in lymphocyte development".Immunology.110(4): 411–420.doi:10.1111/j.1365-2567.2003.01756.x.PMC1783068.PMID14632637.S2CID40885940.
  24. ^abMurphy K (2012).Janeway's immunobiology.Paul Travers, Mark Walport, Charles Janeway (8th ed.). New York: Garland Science.ISBN978-0-8153-4243-4.OCLC733935898.
  25. ^Yasuda T, Tezuka T, Maeda A, Inazu T, Yamanashi Y, Gu H, et al. (July 2002)."Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells".The Journal of Experimental Medicine.196(1): 51–63.doi:10.1084/jem.20020068.PMC2194016.PMID12093870.
  26. ^Hashimoto S, Iwamatsu A, Ishiai M, Okawa K, Yamadori T, Matsushita M, et al. (October 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.doi:10.1182/blood.V94.7.2357.419k40_2357_2364.PMID10498607.S2CID21014231.
  27. ^Hendriks RW, Kersseboom R (February 2006). "Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells".Seminars in Immunology.18(1): 67–76.doi:10.1016/j.smim.2005.10.002.PMID16300960.
  28. ^"BLNK B cell linker [Homo sapiens (human)] - Gene - NCBI".www.ncbi.nlm.nih.gov.Retrieved2023-03-07.
  29. ^Geahlen RL (July 2009)."Syk and pTyr'd: Signaling through the B cell antigen receptor".Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.1793(7): 1115–1127.doi:10.1016/j.bbamcr.2009.03.004.PMC2700185.PMID19306898.
  30. ^Fusaki N, Tomita S, Wu Y, Okamoto N, Goitsuka R, Kitamura D, Hozumi N (May 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.PMID10820378.
  31. ^Chiu CW, Dalton M, Ishiai M, Kurosaki T, Chan AC (December 2002)."BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins".The EMBO Journal.21(23): 6461–6472.doi:10.1093/emboj/cdf658.PMC136961.PMID12456653.
  32. ^Watanabe S, Take H, Takeda K, Yu ZX, Iwata N, Kajigaya S (November 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.PMID11071869.
  33. ^Tsuji S, Okamoto M, Yamada K, Okamoto N, Goitsuka R, Arnold R, et al. (August 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.PMC2193495.PMID11514608.
  34. ^Oellerich T, Grønborg M, Neumann K, Hsiao HH, Urlaub H, Wienands J (July 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.PMC2709198.PMID19372136.

Further reading

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