B-cell linker

B-cell linker (BLNK) protein is expressed in B cells and macrophages and plays a large role in B cell receptor signaling.[5] Like all adaptor proteins, BLNK has no known intrinsic enzymatic activity.[6] Its function is to temporally and spatially coordinate and regulate downstream signaling effectors in B 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 the BLNK gene[8][10] and is also known as SLP-65,[11] BASH,[12] and BCA.[13]

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
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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and localization

BLNK consists of a N-terminal leucine zipper motif followed by an acidic region, a proline-rich region, and a C-terminal SH2 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 from lymphoctye cytosolic protein 2, also known as LCP-2 or SLP-76, which plays a similar role in T cell receptor signaling.[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-ITAM phospho-tyrosine on the cytoplasmic domain of CD79A, which is a part of Igα and the B cell receptor complex.[17][18][19]

Function
BLNK’s function and interaction shown in a schematic of BCR signaling pathways. BCR antigen recognition activates Src family kinases, including the SYK and BTK tyrosine kinases. Syk then phosphorylates BLNK, which can recruit downstream signaling molecules such as Grb2, PLCG2, Vav and Nck.

BLNK's function and importance in B cell development were first illustrated in BLNK deficient DT40 cells, a chicken B cell line.[7] DT40 cells had interrupted B cell development: there was no calcium mobilization response in the B cell, impaired activation of the mitogen-activated protein (MAP) kinases p38, JNK, and somewhat inhibited ERK activation upon (BCR) activation as compared to wild type DT40 cells.[7] In knockout 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 with Bruton's tyrosine kinase (Btk) [25][26] and regulation of the pre-B cell checkpoint.[14][27]

Phosphorylation and interactions

The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five of which are found in humans.[28] Evidence suggests that BLNK is phosphorylated by the tyrosine-protein kinase Syk after B cell receptor activation.[8][9][24][29] Phosphorylation of these residues provides docking sites necessary for downstream protein-protein interactions between BLNK and the SH2 domain-containing proteins Grb2,[8][11][17][30] PLCG2, Btk, the Vav protein family, and Nck.[31][9][8] BLNK has also been shown to interact with SH3KBP1[32] and MAP4K1.[33] 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.[34]

References
  1. GRCh38: Ensembl release 89: ENSG00000095585 - Ensembl, May 2017
  2. GRCm38: 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. Köhler 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. PMID 15654340. S2CID 10708737.
  6. Borowicz 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. PMID 32734639. S2CID 220892370.
  7. Ishiai 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. PMID 10023776.
  8. Fu 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. PMID 9697839.
  9. Hong 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. PMID 12077122.
  10. "Entrez Gene: BLNK B-cell linker".
  11. Wienands 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. PMC 2213353. PMID 9705962.
  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. PMID 9834055. S2CID 38459642.
  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. PMID 9683264.
  14. Herzog 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. PMID 16760574. S2CID 11515343.
  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. PMID 16493428. S2CID 22368341.
  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. PMID 12670393. S2CID 33990866.
  17. Engels 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. PMID 11449366. S2CID 31494726.
  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. PMC 133735. PMID 11909947.
  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. PMID 15699130.
  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. PMID 10591180.
  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. PMID 10583957.
  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. PMID 10583958.
  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. PMC 1783068. PMID 14632637. S2CID 40885940.
  24. Murphy K (2012). Janeway's immunobiology. Paul Travers, Mark Walport, Charles Janeway (8th ed.). New York: Garland Science. ISBN 978-0-8153-4243-4. OCLC 733935898.
  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. PMC 2194016. PMID 12093870.
  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. PMID 10498607. S2CID 21014231.
  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. PMID 16300960.
  28. "BLNK B cell linker [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-03-07.
  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. PMC 2700185. PMID 19306898.
  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. PMID 10820378.
  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. PMC 136961. PMID 12456653.
  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. PMID 11071869.
  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. PMC 2193495. PMID 11514608.
  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. PMC 2709198. PMID 19372136.

Further reading
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