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

• OBJECTIVE: To investigate, in a human urinary tract cell line, the interaction of Toll-like receptor (TLR) signals with cytoplasmic adapter proteins MyD88 and bacillus Calmette-Guérin (BCG), and evaluate the epithelial cytokine response to BCG infection [10].

Biological context of BLNK

• In addition, BLNK(-)/- B cells exhibit a high rate of spontaneous apoptosis in culture [11].
• This interaction requires Tyr(379) of HPK1 and the Src homology 2 (SH2) domain of BLNK/SLP-76 [12].
• 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 [11].
• BLNK(-/-) mice exhibit an incomplete block in B cell development with a severe inhibition of pro-B to pre-B cell differentiation [13].
• B-cell linker protein (BLNK) is a component of the B-cell receptor (BCR) as well as of the pre-BCR signalling pathway, and BLNK(-/-) mice have a block in B lymphopoiesis at the pro-B/pre-B cell stage [14].

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

• Immunoprecipitation and Western blot analyses revealed that this protein is the B cell linker protein (BLNK), also named SH2 domain leukocyte protein of 65 kDa, and that upon tyrosine phosphorylation BLNK binds to SHP-1-C/S in vitro [16].
• A possible explanation for the involvement of Cbl in PLC-gamma2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell linker protein (BLNK) after BCR ligation [26].
• All 30 primary B-lineage ALL samples studied by RT-PCR expressed BLNK transcripts; all 19 samples studied by Western blotting or flow cytometry expressed BLNK protein [3].
• These data suggest that SLP-65 is part of a BCR transducer complex [27].
• (5) The linear gap penalty, which is most commonly used in sequence alignment, is not supported by our analysis; rather, the power law for the size distribution of indels suggests that an appropriate gap penalty is wk = a + b ln k, where a is the gap creation cost and blnk is the gap extension cost [28].

References