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Gene Review

BLNK  -  B-cell linker

Homo sapiens

Synonyms: AGM4, B-cell adapter containing a SH2 domain protein, B-cell adapter containing a Src homology 2 domain protein, B-cell linker protein, BASH, ...
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Disease relevance of BLNK

  • We report that these signaling molecules are frequently present, and in particular that Syk, BLNK and PLC-gamma2 (absent from Reed-Sternberg cells) are present in the majority of mediastinal B cell lymphomas [1].
  • In contrast, the tumor cells in all cases of lymphocyte predominance Hodgkin disease were positive for Fyn, Syk, BLNK, and PLC-gamma2, and Lyn immunostaining was seen in a minority of biopsies [2].
  • It has been proposed that BLNK deficiency is a primary cause of B-lineage acute lymphoblastic leukemia (ALL) [3].
  • We studied BLNK expression in the leukemic cells from 352 patients with childhood ALL (309 B-lineage; 43 T-lineage) [3].
  • Biochemical analysis of the underlying signaling pathways revealed that EBV infection causes constitutive tyrosine phosphorylation of one of the two SLP-65 isoforms and complex formation between SLP-65 and the protooncoprotein CrkL (CT10 regulator of kinase like) [4].

Psychiatry related information on BLNK

  • Commentary on Bash A (2004) Spirituality: the emperor's new clothes? Journal of Clinical Nursing 13, 11-16 [5].

High impact information on BLNK

  • Tyrosine 96 of SLP-65 was required for this activity [6].
  • This loss is probably due to the incorporation of alternative exons into SLP-65 transcripts, leading to premature stop codons [6].
  • In B cells, an analogous adaptor, BLNK/SLP-65, is required for signaling by the ITAM-containing B cell receptor [7].
  • The immune system and overall growth and development were otherwise normal in this patient, suggesting that BLNK function is highly specific [8].
  • These events promoted Lyn activation and Igbeta phosphorylation and led to the generation of a raft-associated signaling module composed of tyrosine phosphorylated Lyn, Syk, BLNK, PI3K, Btk, VAV, and PLCgamma2 [9].

Chemical compound and disease context of BLNK


Biological context of BLNK


Anatomical context of BLNK

  • An essential role for BLNK in human B cell development [8].
  • Together, these data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function [15].
  • Whereas the SLP-76 and LAT adaptor proteins are expressed in T, natural killer, and myeloid cells and platelets, BLNK is preferentially expressed in B cells and monocytes [15].
  • BLNK(-/-) sIgM(+) cells can develop, seed the peripheral lymphoid tissues and accumulate in numbers overtime [13].
  • A recent report described the complete loss or drastic reduction of BLNK expression in approximately 50% of human childhood pre-B acute lymphoblastic leukaemias (ALL), therefore we investigated BLNK expression in human pre-B ALL cell lines [14].

Associations of BLNK with chemical compounds

  • Taken collectively, our results suggest that BLNK is a physiological substrate of SHP-1 in B cells and that SHP-1 selectively regulates c-Jun NH2-terminal kinase activation [16].
  • Tyrosine-phosphorylated SLP-65 assembles intracellular signaling complexes such as the Ca(2 +) initiation complex encompassing phospholipase C-gamma2 and Bruton's tyrosine kinase [17].
  • Also in primary leukemia cells, truncated SLP65 is expressed before but not after treatment of the patients with STI571 [18].
  • Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are cytoplasmic adapter proteins that link a wide variety of cell surface receptors to the apoptotic signaling cascade [19].
  • Recent studies indicated that NF-kappa B is also involved in the cell cycle regulation, and high expression of c-Rel results in a cell cycle arrest at the G1/S-phase transition (Bash, J., Zong, W,-X., and Gelinas, C. (1997) Mol. Cell. Biol. 17, 6526-6536) [20].

Physical interactions of BLNK

  • Coimmunoprecipitation experiments using mammalian cells revealed that CIN85 directly bound to BLNK through its SH3 domains [21].
  • Together, our results suggest a central role for the SH2(N) domain in directing PLC-gamma 2 into the close proximity of BCR signaling complex by its association with BLNK, whereby PLC-gamma 2 becomes tyrosine phosphorylated and thereby activated [22].

Enzymatic interactions of BLNK

  • The interaction is mediated by the Src homology 2 domain of SLP-65 and the phosphorylated Ig-alpha tyrosine 204, which is located outside of the immunoreceptor tyrosine-based activation motif [17].

Other interactions of BLNK

  • Because B cells in these models are predominantly immature, experiments were also performed using mature B cells expressing low levels of Btk and BLNK [23].
  • Hence, these data suggest a functional overlap between BLNK and SLP-76, while emphasizing the difference in requirement for additional adaptor molecules in their targeting to GEMs [24].
  • Immunostaining analysis showed that CIN85 and BLNK were colocalized in the cytoplasm [21].
  • In contrast to SLP-76, BLNK did not require Grb2 families for its recruitment to GEMs [24].
  • Here we demonstrate that, in the BCR-expressing myeloma line J558L mu 3, CD72 expression reduces the BCR ligation-induced phosphorylation of the BCR component Ig alpha/Ig beta and its cytoplasmic effectors Syk and SLP-65 [25].

Analytical, diagnostic and therapeutic context of BLNK


  1. Expression pattern of intracellular leukocyte-associated proteins in primary mediastinal B cell lymphoma. Marafioti, T., Pozzobon, M., Hansmann, M.L., Gaulard, P., Barth, T.F., Copie-Bergman, C., Roberton, H., Ventura, R., Martín-Subero, J.I., Gascoyne, R.D., Pileri, S.A., Siebert, R., Hsi, E.D., Natkunam, Y., Möller, P., Mason, D.Y. Leukemia (2005) [Pubmed]
  2. Expression of intracellular signaling molecules in classical and lymphocyte predominance Hodgkin disease. Marafioti, T., Pozzobon, M., Hansmann, M.L., Delsol, G., Pileri, S.A., Mason, D.Y. Blood (2004) [Pubmed]
  3. Expression of the adaptor protein BLNK/SLP-65 in childhood acute lymphoblastic leukemia. Imai, C., Ross, M.E., Reid, G., Coustan-Smith, E., Schultz, K.R., Pui, C.H., Downing, J.R., Campana, D. Leukemia (2004) [Pubmed]
  4. Epstein-Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module. Engels, N., Merchant, M., Pappu, R., Chan, A.C., Longnecker, R., Wienands, J. J. Exp. Med. (2001) [Pubmed]
  5. Commentary on Bash A (2004) Spirituality: the emperor's new clothes? Journal of Clinical Nursing 13, 11-16. McSherry, W. Journal of clinical nursing. (2005) [Pubmed]
  6. Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia. Jumaa, H., Bossaller, L., Portugal, K., Storch, B., Lotz, M., Flemming, A., Schrappe, M., Postila, V., Riikonen, P., Pelkonen, J., Niemeyer, C.M., Reth, M. Nature (2003) [Pubmed]
  7. Mechanisms of signaling by the hematopoietic-specific adaptor proteins, SLP-76 and LAT and their B cell counterpart, BLNK/SLP-65. Yablonski, D., Weiss, A. Adv. Immunol. (2001) [Pubmed]
  8. An essential role for BLNK in human B cell development. Minegishi, Y., Rohrer, J., Coustan-Smith, E., Lederman, H.M., Pappu, R., Campana, D., Chan, A.C., Conley, M.E. Science (1999) [Pubmed]
  9. Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex. Guo, B., Kato, R.M., Garcia-Lloret, M., Wahl, M.I., Rawlings, D.J. Immunity (2000) [Pubmed]
  10. Uroepithelial cells can directly respond to Mycobacterium bovis bacillus Calmette-Guérin through Toll-like receptor signalling. Miyazaki, J., Kawai, K., Oikawa, T., Johraku, A., Hattori, K., Shimazui, T., Akaza, H. BJU international. (2006) [Pubmed]
  11. 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. Tan, J.E., Wong, S.C., Gan, S.K., Xu, S., Lam, K.P. J. Biol. Chem. (2001) [Pubmed]
  12. Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes. Sauer, K., Liou, J., Singh, S.B., Yablonski, D., Weiss, A., Perlmutter, R.M. J. Biol. Chem. (2001) [Pubmed]
  13. B cell development and activation defects resulting in xid-like immunodeficiency in BLNK/SLP-65-deficient mice. Xu, S., Tan, J.E., Wong, E.P., Manickam, A., Ponniah, S., Lam, K.P. Int. Immunol. (2000) [Pubmed]
  14. Deficiency of BLNK hampers PLC-gamma2 phosphorylation and Ca2+ influx induced by the pre-B-cell receptor in human pre-B cells. Taguchi, T., Kiyokawa, N., Takenouch, H., Matsui, J., Tang, W.R., Nakajima, H., Suzuki, K., Shiozawa, Y., Saito, M., Katagiri, Y.U., Takahashi, T., Karasuyama, H., Matsuo, Y., Okita, H., Fujimoto, J. Immunology (2004) [Pubmed]
  15. Functional complementation of BLNK by SLP-76 and LAT linker proteins. Wong, J., Ishiai, M., Kurosaki, T., Chan, A.C. J. Biol. Chem. (2000) [Pubmed]
  16. 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. Mizuno, K., Tagawa, Y., Mitomo, K., Arimura, Y., Hatano, N., Katagiri, T., Ogimoto, M., Yakura, H. J. Immunol. (2000) [Pubmed]
  17. Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha. Engels, N., Wollscheid, B., Wienands, J. Eur. J. Immunol. (2001) [Pubmed]
  18. The BCR-ABL1 kinase bypasses selection for the expression of a pre-B cell receptor in pre-B acute lymphoblastic leukemia cells. Klein, F., Feldhahn, N., Harder, L., Wang, H., Wartenberg, M., Hofmann, W.K., Wernet, P., Siebert, R., Müschen, M. J. Exp. Med. (2004) [Pubmed]
  19. Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-kappaB-dependent pathway. Wang, X., Wang, Q., Hu, W., Evers, B.M. Oncogene (2004) [Pubmed]
  20. Association of Cdk2/cyclin E and NF-kappa B complexes at G1/S phase. Chen, E., Li, C.C. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  21. Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes. Watanabe, S., Take, H., Takeda, K., Yu, Z.X., Iwata, N., Kajigaya, S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  22. Cutting edge: association of phospholipase C-gamma 2 Src homology 2 domains with BLNK is critical for B cell antigen receptor signaling. Ishiai, M., Sugawara, H., Kurosaki, M., Kurosaki, T. J. Immunol. (1999) [Pubmed]
  23. B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton's Tyrosine Kinase. Hinman, R.M., Bushanam, J.N., Nichols, W.A., Satterthwaite, A.B. J. Immunol. (2007) [Pubmed]
  24. Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane. Ishiai, M., Kurosaki, M., Inabe, K., Chan, A.C., Sugamura, K., Kurosaki, T. J. Exp. Med. (2000) [Pubmed]
  25. SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates. Adachi, T., Wienands, J., Wakabayashi, C., Yakura, H., Reth, M., Tsubata, T. J. Biol. Chem. (2001) [Pubmed]
  26. Cbl suppresses B cell receptor-mediated phospholipase C (PLC)-gamma2 activation by regulating B cell linker protein-PLC-gamma2 binding. Yasuda, T., Maeda, A., Kurosaki, M., Tezuka, T., Hironaka, K., Yamamoto, T., Kurosaki, T. J. Exp. Med. (2000) [Pubmed]
  27. SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation. Wienands, J., Schweikert, J., Wollscheid, B., Jumaa, H., Nielsen, P.J., Reth, M. J. Exp. Med. (1998) [Pubmed]
  28. The size distribution of insertions and deletions in human and rodent pseudogenes suggests the logarithmic gap penalty for sequence alignment. Gu, X., Li, W.H. J. Mol. Evol. (1995) [Pubmed]
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