B-cell linker

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. The leucine zipper motif allows BLNK to localize to the plasma membrane, presumably by coiled-coil interactions with a membrane protein. 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. 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. 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.

Function

BLNK's function and importance in B cell development were first illustrated in BLNK deficient DT40 cells, a chicken B cell line. 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. In knockout mice, BLNK deficiency results in a partial block in B cell development, and in humans BLNK deficiency results in a much more profound block in B cell development.

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

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

Phosphorylation and interactions

The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five of which are found in humans. Evidence suggests that BLNK is phosphorylated by the tyrosine-protein kinase Syk after B cell receptor activation. Phosphorylation of these residues provides docking sites necessary for downstream protein-protein interactions between BLNK and the SH2 domain-containing proteins Grb2, PLCG2, Btk, the Vav protein family, and Nck. BLNK has also been shown to interact with SH3KBP1 and MAP4K1. 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.

References

References

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