Disease relevance of Blnk

• Our recent findings of defective SLP-65 expression in approximately 50% of childhood pre-B acute lymphoblastic leukemias and spontaneous pre-B cell lymphoma development in SLP-65-/- mice demonstrate that SLP-65 acts as a tumor suppressor [1].
• In the mouse, the downstream signaling molecules SLP-65 and Btk cooperate to limit proliferation and induce differentiation of pre-B cells, thereby acting as tumor suppressors to prevent pre-B cell leukemia [2].
• To determine whether macrophages functioned normally in vivo, we infected WT and SLP-76(-/-) SLP-65(-/-) mice with sublethal doses of Listeria monocytogenes (LM), a bacterium against which the initial host defense is provided by activated macrophages [3].
• A new tumor-associated antigen expressed on breast carcinomas, defined by monoclonal antibody BCA 227 [4].
• All these data are in favor of the use of mAb BCA 227 as an immunodiagnostic tool for breast cancer [4].

High impact information on Blnk

• B cell development in BLNK-/- mice was blocked at the transition from B220+CD43+ progenitor B to B220+CD43- precursor B cells [5].
• In B cells, B cell linker protein (BLNK) links the B cell receptor (BCR)-activated Syk kinase to the phosphoinositide and mitogen-activated kinase pathways [5].
• Together, our results suggest that the adaptor proteins LAT and SLP-76 are involved in pre-BCR signaling, thereby rescuing arrested murine SLP-65(-/-) pre-B cells [6].
• Reconstitution of LAT or SLP-65 expression in SLP-65/LAT(-/-) pre-B cells restored their calcium (Ca2+) mobilization capacity, led to downregulation of surface pre-BCR, and induced differentiation to BCR+ cells [6].
• Ig(mu)(+) Pax5(-/-) pro-B cells expressing a BLNK-estrogen receptor fusion protein initiated signaling immediately upon hormone addition, which facilitated analysis of pre-BCR-induced gene expression changes [7].

Chemical compound and disease context of Blnk

• When treated with cinnamaldehyde for 10 weeks, hepatic tumor development was delayed with 2'-benzoyloxycinnamaldehyde (BCA) compared with control hepatocellular carcinoma formation [8].

Biological context of Blnk

• These results suggest that Igalpha non-ITAM tyrosine 204 promotes a distinct cellular response, namely T-independent B cell proliferation and differentiation via phosphorylation of the adaptor BLNK [9].
• Restoration of BLNK expression in Ig(mu) transgenic Pax5(-/-) pro-B cells resulted in constitutive pre-BCR signaling and increased cell proliferation without inducing progression to the pre-B cell stage [7].
• During signal transduction through the B cell antigen receptor (BCR), several signaling elements are brought together by the adaptor protein SLP-65 [10].
• Finally, splenic B cells in BCR-transgenic BLNK(-/-) mice are predominantly of the transitional B cell phenotype and are rapidly lost from the peripheral B cell pool [11].
• B cell linker (BLNK) protein is a component of the B cell receptor (BCR) signaling pathway and BLNK(-/-) mice have a block in B lymphopoiesis at the pro-B/pre-B cell stage [11].

Anatomical context of Blnk

• In contrast, Blnk is necessary for B-cell development and activation [12].
• R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells [13].
• We show that murine bone marrow-derived macrophages express both SLP-76 and BLNK [14].
• Together, the data demonstrate the synergistic role of SLP65 and Btk in B cell development and describe a situation where large numbers of preB cell receptor-positive cells accumulate in the bone marrow and spleen [15].
• During B-cell development in the mouse, Bruton tyrosine kinase (Btk) and the adaptor protein SLP-65 (Src homology 2 [SH2] domain-containing leukocyte protein of 65 kDa) limit the expansion and promote the differentiation of pre-B cells [16].

Associations of Blnk with chemical compounds

• These results show that SLP65/BLNK is not absolutely essential for Ca(2+) induction in B cells, because the deficiency of this adapter can be by-passed by the additional deletion of an inhibitory receptor [17].
• BCA-induced apoptosis was blocked by pretreatment of cells with anti-oxidants, glutathione, or N-acetyl-cysteine [18].
• Acetylation of BCA with acetic anhydride converts all 18 lysine-epsilon-NH(3)(+) groups to lysine-epsilon-NHCOCH(3) groups and generates BCA-Ac(18) [19].
• This study compares the folding of two polypeptides--bovine carbonic anhydrase (BCA) and peracetylated BCA (BCA-Ac(18))--having the same sequence of amino acids but differing by 18 formal units of charge, from a solution containing denaturing concentrations of sodium dodecyl sulfate (SDS) [19].
• Regulation of BLNK recruitment was dependent upon the Grap2 proline-rich domain, while modulation of phosphorylation was dependent upon both the proline-rich and SH2 domains [20].

Regulatory relationships of Blnk

• Haploinsufficiency of B cell linker protein enhances B cell signaling defects in mice expressing a limiting dosage of Bruton's tyrosine kinase [21].
• Toll-like receptor (TLR) can activate dendritic cells (DC) through common signaling pathways requiring a cytoplasmic adapter, MyD88 [22].

Other interactions of Blnk

• Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene [7].
• These findings demonstrate that Btk cooperates with SLP-65 as a tumor suppressor in pre-B cells [1].
• This implies that SLP65/BLNK is not the sole target of SHP-1 in the regulation of the Ca(2+) signaling strength [17].
• Selective ligation of FcgammaRI and FcgammaRII/III resulted in tyrosine phosphorylation of both SLP-76 and BLNK [14].
• Subsequent analysis demonstrated that phosphorylation of Y(176)/Y(204) recruited the B cell linker protein, Vav, and Grb2 [23].

Analytical, diagnostic and therapeutic context of Blnk

• The B cell-restricted adaptor protein BASH (also termed BLNK/SLP-65) is rapidly phosphorylated by the tyrosine kinase Syk after BCR ligation and binds to various signaling proteins [24].
• Characterization of the B cell-specific adaptor SLP-65 and other protein tyrosine kinase substrates by two-dimensional gel electrophoresis [25].
• Both BCA and BCA-Ac(18) are catalytically active, and circular dichroism spectroscopy (CD) suggests that they have similar secondary and tertiary structures [19].
• HCA and BCA strongly inhibited in vitro growth of 29 kinds of human cancer cells and in vivo growth of SW-620 human tumor xenograft without the loss of body weight in nude mice [26].

References