B-cell linker

The B-cell linker protein is encoded by the BLNK gene[4][5] and is an adaptor protein also known as SLP-65,[6] BASH,[7] and BCA.[8] 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.[9] 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.

BLNK
Available structures
PDBOrtholog search: PDBe RCSB
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
Gene location (Human)
Chr.Chromosome 10 (human)[1]
Band10q24.1Start96,191,702 bp[1]
End96,271,587 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

29760

17060

Ensembl

ENSG00000095585

n/a

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 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

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.[10] In knockout mice, BLNK deficiency results in a partial block in B-cell development,[11][12] and in humans BLNK deficiency results in a much more profound block in B-cell development.[13]

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][5]

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.[14] 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.[15][16][17]

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.[18] 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.[19]

Interactions

B-cell linker has been shown to interact with Grb2,[4][6][15][20] SH3KBP1,[21] CD79A,[15][16] MAP4K1[22] and Bruton's tyrosine kinase.[23][24]

Post-translational modification
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gollark: 1
gollark: skip

References
  1. GRCh38: Ensembl release 89: ENSG00000095585 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. 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.
  5. "Entrez Gene: BLNK B-cell linker".
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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. doi:10.1182/blood.V94.7.2357.419k40_2357_2364. PMID 10498607.

Further reading
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