Biology:B-cell linker

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

B-cell linker (BLNK) protein is expressed in B cells and macrophages and plays a large role in B cell receptor signaling.[1] Like all adaptor proteins, BLNK has no known intrinsic enzymatic activity.[2] 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.[3] Binding of these downstream effectors is dependent on BLNK phosphorylation.[4][5] BLNK is encoded by the BLNK gene[4][6] and is also known as SLP-65,[7] BASH,[8] and BCA.[9]

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.[10][1] The leucine zipper motif allows BLNK to localize to the plasma membrane, presumably by coiled-coil interactions with a membrane protein.[1] 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.[11] 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.[12] 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.[13][14][15]

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.[3] 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.[3] In knockout mice, BLNK deficiency results in a partial block in B cell development,[16][17] and in humans BLNK deficiency results in a much more profound block in B cell development.[18][1]

Linker or adaptor proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins.[2] BLNK is essential for normal B-cell development as part of the B cell receptor signaling pathway. [supplied by OMIM][6][19][20]

Evidence also suggests that BLNK may have tumor suppressive activity through its interaction with Bruton's tyrosine kinase (Btk) [21][22] and regulation of the pre-B cell checkpoint.[10][23]

Phosphorylation and interactions

The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five of which are found in humans.[24] Evidence suggests that BLNK is phosphorylated by the tyrosine-protein kinase Syk after B cell receptor activation.[4][5][20][25] Phosphorylation of these residues provides docking sites necessary for downstream protein-protein interactions between BLNK and the SH2 domain-containing proteins Grb2,[4][7][13][26] PLCG2, Btk, the Vav protein family, and Nck.[27][5][4] BLNK has also been shown to interact with SH3KBP1[28] and MAP4K1.[29] 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.[30]

References

  1. ↑ 1.0 1.1 1.2 1.3 "A leucine zipper in the N terminus confers membrane association to SLP-65". Nature Immunology 6 (2): 204–210. February 2005. doi:10.1038/ni1163. PMID 15654340. 
  2. ↑ 2.0 2.1 "Adaptor proteins: Flexible and dynamic modulators of immune cell signalling". Scandinavian Journal of Immunology 92 (5): e12951. November 2020. doi:10.1111/sji.12951. PMID 32734639. 
  3. ↑ 3.0 3.1 3.2 "BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells". Immunity 10 (1): 117–125. January 1999. doi:10.1016/S1074-7613(00)80012-6. PMID 10023776. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "BLNK: a central linker protein in B cell activation". Immunity 9 (1): 93–103. July 1998. doi:10.1016/S1074-7613(00)80591-9. PMID 9697839. 
  5. ↑ 5.0 5.1 5.2 "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" (in English). The Journal of Biological Chemistry 277 (35): 31703–31714. August 2002. doi:10.1074/jbc.M201362200. PMID 12077122. 
  6. ↑ 6.0 6.1 "Entrez Gene: BLNK B-cell linker". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29760. 
  7. ↑ 7.0 7.1 "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. August 1998. doi:10.1084/jem.188.4.791. PMID 9705962. 
  8. ↑ "BASH, a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius". Journal of Immunology 161 (11): 5804–5808. December 1998. doi:10.4049/jimmunol.161.11.5804. PMID 9834055. 
  9. ↑ "bca: an activation-related B-cell gene". Molecular Immunology 35 (1): 55–63. January 1998. doi:10.1016/s0161-5890(98)00008-x. PMID 9683264. 
  10. ↑ 10.0 10.1 "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. 2006. doi:10.1385/ir:34:2:143. PMID 16760574. 
  11. ↑ "SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond". Nature Reviews. Immunology 6 (1): 67–78. January 2006. doi:10.1038/nri1750. PMID 16493428. 
  12. ↑ "Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation". Immunological Reviews 192 (1): 32–41. April 2003. doi:10.1034/j.1600-065X.2003.00005.x. PMID 12670393. 
  13. ↑ 13.0 13.1 "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. July 2001. doi:10.1002/1521-4141(200107)31:7<2126::AID-IMMU2126>3.0.CO;2-O. PMID 11449366. 
  14. ↑ "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. April 2002. doi:10.1128/MCB.22.8.2524-2535.2002. PMID 11909947. 
  15. ↑ "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. February 2005. doi:10.4049/jimmunol.174.4.2012. PMID 15699130. 
  16. ↑ "Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65". Immunity 11 (5): 547–554. November 1999. doi:10.1016/S1074-7613(00)80130-2. PMID 10591180. 
  17. ↑ "Requirement for B cell linker protein (BLNK) in B cell development". Science 286 (5446): 1949–1954. December 1999. doi:10.1126/science.286.5446.1949. PMID 10583957. 
  18. ↑ "An essential role for BLNK in human B cell development". Science 286 (5446): 1954–1957. December 1999. doi:10.1126/science.286.5446.1954. PMID 10583958. 
  19. ↑ "B-cell antigen-receptor signalling in lymphocyte development". Immunology 110 (4): 411–420. December 2003. doi:10.1111/j.1365-2567.2003.01756.x. PMID 14632637. 
  20. ↑ 20.0 20.1 Janeway's immunobiology. Paul Travers, Mark Walport, Charles Janeway (8th ed.). New York: Garland Science. 2012. ISBN 978-0-8153-4243-4. OCLC 733935898. https://www.worldcat.org/oclc/733935898. 
  21. ↑ "Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells". The Journal of Experimental Medicine 196 (1): 51–63. July 2002. doi:10.1084/jem.20020068. PMID 12093870. 
  22. ↑ "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. October 1999. doi:10.1182/blood.V94.7.2357.419k40_2357_2364. PMID 10498607. 
  23. ↑ "Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells". Seminars in Immunology 18 (1): 67–76. February 2006. doi:10.1016/j.smim.2005.10.002. PMID 16300960. 
  24. ↑ "BLNK B cell linker [Homo sapiens (human) - Gene - NCBI"] (in en). https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=29760. 
  25. ↑ "Syk and pTyr'd: Signaling through the B cell antigen receptor". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1793 (7): 1115–1127. July 2009. doi:10.1016/j.bbamcr.2009.03.004. PMID 19306898. 
  26. ↑ "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. May 2000. doi:10.1002/(SICI)1521-4141(200005)30:5<1326::AID-IMMU1326>3.0.CO;2-Q. PMID 10820378. 
  27. ↑ "BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins". The EMBO Journal 21 (23): 6461–6472. December 2002. doi:10.1093/emboj/cdf658. PMID 12456653. 
  28. ↑ "Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes". Biochemical and Biophysical Research Communications 278 (1): 167–174. November 2000. doi:10.1006/bbrc.2000.3760. PMID 11071869. https://zenodo.org/record/1229524. 
  29. ↑ "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. August 2001. doi:10.1084/jem.194.4.529. PMID 11514608. 
  30. ↑ "SLP-65 phosphorylation dynamics reveals a functional basis for signal integration by receptor-proximal adaptor proteins". Molecular & Cellular Proteomics 8 (7): 1738–1750. July 2009. doi:10.1074/mcp.M800567-MCP200. PMID 19372136. 

Further reading

External links



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