The B-cell linker protein is encoded by the BLNKgene[1][2] and is an adaptor protein also known as SLP-65,[3]BASH,[4] and BCA.[5] 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.[6] 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.
The function of BLNK was first illustrated in BLNK deficient DT40 cells, a chickenB-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.[7] In knockout mice, BLNK deficiency results in a partial block in B-cell development,[8][9] and in humans BLNK deficiency results in a much more profound block in B-cell development.[10]
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][2]
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.[11] 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.[12][13][14]
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.[15] 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.[16]
↑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. PMID9834055.
↑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. PMID9683264.
↑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. PMID16493428.
↑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. PMID10023776.
↑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. PMID10591180.
↑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. PMID10583957.
↑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. PMID10583958.
↑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. PMID15654340.
↑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. PMID15699130.
↑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. PMID10820378.
↑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. PMID11071869.
↑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. PMID10498607.
Further reading
Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Fu C, Chan AC (1997). "Identification of two tyrosine phosphoproteins, pp70 and pp68, which interact with phospholipase Cgamma, Grb2, and Vav after B cell antigen receptor activation". J. Biol. Chem. 272 (43): 27362–8. doi:10.1074/jbc.272.43.27362. PMID9341187.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Hashimoto S, Iwamatsu A, Ishiai M, et al. (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): 2357–64. PMID10498607.
Mizuno K, Tagawa Y, Mitomo K, et al. (2000). "Src homology region 2 (SH2) domain-containing phosphatase-1 dephosphorylates B cell linker protein/SH2 domain leukocyte protein of 65 kDa and selectively regulates c-Jun NH2-terminal kinase activation in B cells". J. Immunol. 165 (3): 1344–51. doi:10.4049/jimmunol.165.3.1344. PMID10903736.
Guo B, Kato RM, Garcia-Lloret M, et al. (2000). "Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex". Immunity. 13 (2): 243–53. doi:10.1016/S1074-7613(00)00024-8. PMID10981967.
Watanabe S, Take H, Takeda K, et al. (2001). "Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes". Biochem. Biophys. Res. Commun. 278 (1): 167–74. doi:10.1006/bbrc.2000.3760. PMID11071869.
Tan JE, Wong SC, Gan SK, et al. (2001). "The adaptor protein BLNK is required for b cell antigen receptor-induced activation of nuclear factor-kappa B and cell cycle entry and survival of B lymphocytes". J. Biol. Chem. 276 (23): 20055–63. doi:10.1074/jbc.M010800200. PMID11274146.
Adachi T, Wienands J, Wakabayashi C, et al. (2001). "SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates". J. Biol. Chem. 276 (28): 26648–55. doi:10.1074/jbc.M100997200. PMID11356834.
Sauer K, Liou J, Singh SB, et al. (2002). "Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes". J. Biol. Chem. 276 (48): 45207–16. doi:10.1074/jbc.M106811200. PMID11487585.
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