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.{{cite journal | vauthors = Köhler F, Storch B, Kulathu Y, Herzog S, Kuppig S, Reth M, Jumaa H | title = A leucine zipper in the N terminus confers membrane association to SLP-65 | journal = Nature Immunology | volume = 6 | issue = 2 | pages = 204–210 | date = February 2005 | pmid = 15654340 | pmc = | doi = 10.1038/ni1163 | s2cid = 10708737 }} Like all adaptor proteins, BLNK has no known intrinsic enzymatic activity.{{cite journal | vauthors = Borowicz P, Chan H, Hauge A, Spurkland A | title = Adaptor proteins: Flexible and dynamic modulators of immune cell signalling | journal = Scandinavian Journal of Immunology | volume = 92 | issue = 5 | pages = e12951 | date = November 2020 | pmid = 32734639 | doi = 10.1111/sji.12951 | s2cid = 220892370 | hdl = 10852/82328 | hdl-access = free }} 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. Binding of these downstream effectors is dependent on BLNK phosphorylation.{{cite journal | vauthors = Hong JJ, Yankee TM, Harrison ML, Geahlen RL | title = 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 | language = English | journal = The Journal of Biological Chemistry | volume = 277 | issue = 35 | pages = 31703–31714 | date = August 2002 | pmid = 12077122 | doi = 10.1074/jbc.M201362200 | doi-access = free }} BLNK is encoded by the BLNK gene{{cite journal | vauthors = 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 | date = July 1998 | pmid = 9697839 | doi = 10.1016/S1074-7613(00)80591-9 | doi-access = free }}{{cite web | title = Entrez Gene: BLNK B-cell linker| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29760| access-date = }} and is also known as SLP-65,{{cite journal | vauthors = Wienands J, Schweikert J, Wollscheid B, Jumaa H, Nielsen PJ, Reth 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 | date = August 1998 | pmid = 9705962 | pmc = 2213353 | doi = 10.1084/jem.188.4.791 }} BASH,{{cite journal | vauthors = Goitsuka R, Fujimura Y, Mamada H, Umeda A, Morimura T, Uetsuka K, Doi K, Tsuji S, Kitamura D | display-authors = 6 | 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 | date = December 1998 | pmid = 9834055 | doi = 10.4049/jimmunol.161.11.5804 | s2cid = 38459642 | doi-access = free }} and BCA.{{cite journal | vauthors = Gangi-Peterson L, Peterson SN, Shapiro LH, Golding A, Caricchio R, Cohen DI, Margulies DH, Cohen PL | display-authors = 6 | title = bca: an activation-related B-cell gene | journal = Molecular Immunology | volume = 35 | issue = 1 | pages = 55–63 | date = January 1998 | pmid = 9683264 | doi = 10.1016/s0161-5890(98)00008-x }}

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.{{cite journal | vauthors = Herzog S, Storch B, Jumaa H | title = Dual role of the adaptor protein SLP-65: organizer of signal transduction and tumor suppressor of pre-B cell leukemia | journal = Immunologic Research | volume = 34 | issue = 2 | pages = 143–155 | date = 2006 | pmid = 16760574 | doi = 10.1385/ir:34:2:143 | s2cid = 11515343 }} The leucine zipper motif allows BLNK to localize to the plasma membrane, presumably by coiled-coil interactions with a membrane protein. 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.{{cite journal | vauthors = Koretzky GA, Abtahian F, Silverman MA | title = SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond | journal = Nature Reviews. Immunology | volume = 6 | issue = 1 | pages = 67–78 | date = January 2006 | pmid = 16493428 | doi = 10.1038/nri1750 | s2cid = 22368341 }} 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.{{cite journal | vauthors = Rudd CE, Raab M | title = Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation | journal = Immunological Reviews | volume = 192 | issue = 1 | pages = 32–41 | date = April 2003 | pmid = 12670393 | doi = 10.1034/j.1600-065X.2003.00005.x | s2cid = 33990866 }} 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.{{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 = European Journal of Immunology | volume = 31 | issue = 7 | pages = 2126–2134 | date = July 2001 | pmid = 11449366 | pmc = | doi = 10.1002/1521-4141(200107)31:7<2126::AID-IMMU2126>3.0.CO;2-O | s2cid = 31494726 }}{{cite journal | vauthors = Kabak S, Skaggs BJ, Gold MR, Affolter M, West KL, Foster MS, Siemasko K, Chan AC, Aebersold R, Clark MR | display-authors = 6 | title = The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways | journal = Molecular and Cellular Biology | volume = 22 | issue = 8 | pages = 2524–2535 | date = April 2002 | pmid = 11909947 | pmc = 133735 | doi = 10.1128/MCB.22.8.2524-2535.2002 }}{{cite journal | vauthors = Pike KA, Ratcliffe MJ | 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 | date = February 2005 | pmid = 15699130 | doi = 10.4049/jimmunol.174.4.2012 | doi-access = free }}

Function

File:B cell signalling.pngs, 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. 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.{{cite journal | vauthors = Ishiai M, Kurosaki M, Pappu R, Okawa K, Ronko I, Fu C, Shibata M, Iwamatsu A, Chan AC, Kurosaki T | display-authors = 6 | title = BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells | journal = Immunity | volume = 10 | issue = 1 | pages = 117–125 | date = January 1999 | pmid = 10023776 | doi = 10.1016/S1074-7613(00)80012-6 | doi-access = free }} In knockout mice, BLNK deficiency results in a partial block in B cell development,{{cite journal | vauthors = Jumaa H, Wollscheid B, Mitterer M, Wienands J, Reth M, Nielsen PJ | title = Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65 | journal = Immunity | volume = 11 | issue = 5 | pages = 547–554 | date = November 1999 | pmid = 10591180 | doi = 10.1016/S1074-7613(00)80130-2 | doi-access = free }}{{cite journal | vauthors = Pappu R, Cheng AM, Li B, Gong Q, Chiu C, Griffin N, White M, Sleckman BP, Chan AC | display-authors = 6 | title = Requirement for B cell linker protein (BLNK) in B cell development | journal = Science | volume = 286 | issue = 5446 | pages = 1949–1954 | date = December 1999 | pmid = 10583957 | doi = 10.1126/science.286.5446.1949 }} and in humans BLNK deficiency results in a much more profound block in B cell development.{{cite journal | vauthors = Minegishi Y, Rohrer J, Coustan-Smith E, Lederman HM, Pappu R, Campana D, Chan AC, Conley ME | display-authors = 6 | title = An essential role for BLNK in human B cell development | journal = Science | volume = 286 | issue = 5446 | pages = 1954–1957 | date = December 1999 | pmid = 10583958 | doi = 10.1126/science.286.5446.1954 }}

Linker or adaptor proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. BLNK is essential for normal B-cell development as part of the B cell receptor signaling pathway. [supplied by OMIM]{{cite journal | vauthors = Wang LD, Clark MR | title = B-cell antigen-receptor signalling in lymphocyte development | journal = Immunology | volume = 110 | issue = 4 | pages = 411–420 | date = December 2003 | pmid = 14632637 | doi = 10.1111/j.1365-2567.2003.01756.x | s2cid = 40885940 | pmc = 1783068 }}{{cite book | vauthors = Murphy K |url=https://www.worldcat.org/oclc/733935898 |title=Janeway's immunobiology |date=2012 |publisher=Garland Science |others=Paul Travers, Mark Walport, Charles Janeway |isbn=978-0-8153-4243-4 |edition=8th |location=New York |oclc=733935898}}

Evidence also suggests that BLNK may have tumor suppressive activity through its interaction with Bruton's tyrosine kinase (Btk) {{cite journal | vauthors = Yasuda T, Tezuka T, Maeda A, Inazu T, Yamanashi Y, Gu H, Kurosaki T, Yamamoto T | display-authors = 6 | title = Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells | journal = The Journal of Experimental Medicine | volume = 196 | issue = 1 | pages = 51–63 | date = July 2002 | pmid = 12093870 | pmc = 2194016 | doi = 10.1084/jem.20020068 }}{{cite journal | vauthors = Hashimoto S, Iwamatsu A, Ishiai M, Okawa K, Yamadori T, Matsushita M, Baba Y, Kishimoto T, Kurosaki T, Tsukada S | display-authors = 6 | 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 | date = October 1999 | pmid = 10498607 | doi = 10.1182/blood.V94.7.2357.419k40_2357_2364 | s2cid = 21014231 }} and regulation of the pre-B cell checkpoint.{{cite journal | vauthors = Hendriks RW, Kersseboom R | title = Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells | journal = Seminars in Immunology | volume = 18 | issue = 1 | pages = 67–76 | date = February 2006 | pmid = 16300960 | doi = 10.1016/j.smim.2005.10.002 }}

Phosphorylation and interactions

The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five of which are found in humans.{{cite web |title=BLNK B cell linker [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=29760 |access-date=2023-03-07 |website=www.ncbi.nlm.nih.gov |language=en}} Evidence suggests that BLNK is phosphorylated by the tyrosine-protein kinase Syk after B cell receptor activation.{{cite journal | vauthors = Geahlen RL | title = Syk and pTyr'd: Signaling through the B cell antigen receptor | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1793 | issue = 7 | pages = 1115–1127 | date = July 2009 | pmid = 19306898 | doi = 10.1016/j.bbamcr.2009.03.004 | pmc = 2700185 }} Phosphorylation of these residues provides docking sites necessary for downstream protein-protein interactions between BLNK and the SH2 domain-containing proteins Grb2,{{cite journal | vauthors = Fusaki N, Tomita S, Wu Y, Okamoto N, Goitsuka R, Kitamura D, Hozumi N | 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 | date = May 2000 | pmid = 10820378 | doi = 10.1002/(SICI)1521-4141(200005)30:5<1326::AID-IMMU1326>3.0.CO;2-Q | doi-access = free }} PLCG2, Btk, the Vav protein family, and Nck.{{cite journal | vauthors = Chiu CW, Dalton M, Ishiai M, Kurosaki T, Chan AC | title = BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins | journal = The EMBO Journal | volume = 21 | issue = 23 | pages = 6461–6472 | date = December 2002 | pmid = 12456653 | pmc = 136961 | doi = 10.1093/emboj/cdf658 }} BLNK has also been shown to interact with SH3KBP1{{cite journal | vauthors = Watanabe S, Take H, Takeda K, Yu ZX, Iwata N, Kajigaya S | 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 | date = November 2000 | pmid = 11071869 | doi = 10.1006/bbrc.2000.3760 | url = https://zenodo.org/record/1229524 }} and MAP4K1.{{cite journal | vauthors = Tsuji S, Okamoto M, Yamada K, Okamoto N, Goitsuka R, Arnold R, Kiefer F, Kitamura D | display-authors = 6 | 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 | date = August 2001 | pmid = 11514608 | pmc = 2193495 | doi = 10.1084/jem.194.4.529 }} 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.{{cite journal | vauthors = Oellerich T, Grønborg M, Neumann K, Hsiao HH, Urlaub H, Wienands J | title = SLP-65 phosphorylation dynamics reveals a functional basis for signal integration by receptor-proximal adaptor proteins | journal = Molecular & Cellular Proteomics | volume = 8 | issue = 7 | pages = 1738–1750 | date = July 2009 | pmid = 19372136 | pmc = 2709198 | doi = 10.1074/mcp.M800567-MCP200 | doi-access = free }}

References

External links

{{UCSC gene info|BLNK}}

Category:Proteins