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.^[5] Like all adaptor proteins, BLNK has no known intrinsic enzymatic activity.^[6] 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.^[7] Binding of these downstream effectors is dependent on BLNK phosphorylation.^[8][9] BLNK is encoded by the BLNK gene^[8][10] and is also known as SLP-65,^[11] BASH,^[12] and BCA.^[13]

BLNK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2EO6
Identifiers
Aliases	BLNK, AGM4, BASH, BLNK-S, LY57, SLP-65, SLP65, bca, B-cell linker, B cell linker
External IDs	OMIM: 604515; MGI: 96878; HomoloGene: 32038; GeneCards: BLNK; OMA:BLNK - orthologs
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q24.1 Start 96,189,171 bp[1] End 96,271,587 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 C3|19 34.26 cM Start 40,917,371 bp[2] End 40,982,978 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in oral cavity corpus epididymis spleen jejunal mucosa duodenum epithelium of nasopharynx appendix mucosa of pharynx lymph node right lobe of liver Top expressed in spleen mesenteric lymph nodes molar left colon seminal vesicula tail of embryo submandibular gland temporal muscle Ileal epithelium tibiofemoral joint More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transmembrane receptor protein tyrosine kinase adaptor activity protein binding Cellular component cytosol membrane cytoplasm intracellular anatomical structure plasma membrane cytoplasmic ribonucleoprotein granule Biological process humoral immune response B cell differentiation intracellular signal transduction B cell activation inflammatory response positive regulation of signal transduction transmembrane receptor protein tyrosine kinase signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 29760 17060 Ensembl ENSG00000095585 ENSMUSG00000061132 UniProt Q8WV28 Q9QUN3 RefSeq (mRNA) NM_001114094 NM_001258440 NM_001258441 NM_001258442 NM_013314 NM_008528 NM_001365054 RefSeq (protein) NP_001107566 NP_001245369 NP_001245370 NP_001245371 NP_037446 NP_032554 NP_001351983 Location (UCSC) Chr 10: 96.19 – 96.27 Mb Chr 19: 40.92 – 40.98 Mb PubMed search [3] [4]
Wikidata
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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.^[14][5] The leucine zipper motif allows BLNK to localize to the plasma membrane, presumably by coiled-coil interactions with a membrane protein.^[5] 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.^[15] 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.^[16] 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.^[17][18][19]

Function

BLNK’s function and interaction shown in a schematic of BCR signaling pathways. BCR antigen recognition activates Src family kinases, 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.^[7] 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.^[7] In knockout mice, BLNK deficiency results in a partial block in B cell development,^[20][21] and in humans BLNK deficiency results in a much more profound block in B cell development.^[22][5]

Linker or adaptor proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins.^[6] BLNK is essential for normal B-cell development as part of the B cell receptor signaling pathway. [supplied by OMIM]^[10][23][24]

Evidence also suggests that BLNK may have tumor suppressive activity through its interaction with Bruton's tyrosine kinase (Btk) ^[25][26] and regulation of the pre-B cell checkpoint.^[14][27]

Phosphorylation and interactions

The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five of which are found in humans.^[28] Evidence suggests that BLNK is phosphorylated by the tyrosine-protein kinase Syk after B cell receptor activation.^{[8][9][24][29]} Phosphorylation of these residues provides docking sites necessary for downstream protein-protein interactions between BLNK and the SH2 domain-containing proteins Grb2,^{[8][11][17][30]} PLCG2, Btk, the Vav protein family, and Nck.^[31][9][8] BLNK has also been shown to interact with SH3KBP1^[32] and MAP4K1.^[33] 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.^[34]