Abstract
LNK is a member of the SH2B family of adaptor proteins and is a non-redundant regulator of cytokine signalling. Cytokines are secreted intercellular messengers that bind to specific receptors on the surface of target cells to activate the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling pathway. Activation of the JAK-STAT pathway leads to proliferative and often inflammatory effects, and so the amplitude and duration of signalling are tightly controlled. LNK binds phosphotyrosine residues to signalling proteins downstream of cytokines and constrains JAK-STAT signalling. Mutations in LNK have been identified in a range of haematological and inflammatory diseases due to increased signalling following the loss of LNK function. Here, we review the regulation of JAK-STAT signalling via the adaptor protein LNK and discuss the role of LNK in haematological diseases.
Highlights
The lymphocyte adaptor protein, LNK ( SH2B3) [1], is a member of the Src homology 2 (SH2) domain-containing adaptor family of proteins, which comprises APS (SH2B1) and SH2B (SH2B2)
The binding of LNK to phosphotyrosine residues on receptors may prevent other proteins from binding and activating downstream pathways, with LNK acting as a competitive inhibitor
In addition to how LNK exerts its activity, it is unclear why, given their similar structures, APS and SH2B appear to upregulate signalling, while LNK is a negative regulator
Summary
The lymphocyte adaptor protein, LNK ( SH2B3) [1], is a member of the SH2 domain-containing adaptor family of proteins, which comprises APS (SH2B1) and SH2B (SH2B2). This family of proteins modulate signalling downstream of cytokines and growth hormones. SH2 domain-containing domain-containing adaptor adaptor family family of of Figure proteins all share the same domain architecture (top) comprising an N-terminal dimerisation doproteins all share the same domain architecture (top) comprising an N-terminal dimerisation domain main (DD), central pleckstrin homology domain (PH) and C-terminal Src homology 2 (SH2) do(DD), central pleckstrin homology domain (PH) and C-terminal Src homology 2 (SH2) domain. LNK directly binds JAKs and receptors via its receptors via its SH2 domain inhibits downstream signalling.
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