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Review
. 2021 Dec 24;15(1):24.
doi: 10.3390/ph15010024.

The Role of LNK (SH2B3) in the Regulation of JAK-STAT Signalling in Haematopoiesis

Rhiannon Morris  1   2 , Liesl Butler  3   4 , Andrew Perkins  3   4 , Nadia J Kershaw  1   2 , Jeffrey J Babon  1   2
Affiliations
Review

The Role of LNK (SH2B3) in the Regulation of JAK-STAT Signalling in Haematopoiesis

Rhiannon Morris et al. Pharmaceuticals (Basel). .

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.

Keywords: JAK-STAT; SH2B3; myeloproliferative neoplasms.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
LNK and the adaptor family of proteins. The SH2 domain-containing adaptor family of proteins all share the same domain architecture (top) comprising an N-terminal dimerisation domain (DD), central pleckstrin homology domain (PH) and C-terminal Src homology 2 (SH2) domain. Schematic diagram of cytokine signalling showing regulators of cytokine signalling and where they act (bottom). Phosphatases and Suppressor of Cytokine Signalling (SOCS) proteins are shown semi-transparently, whereas LNK is shown in solid colour. LNK directly binds JAKs and receptors via its SH2 domain and inhibits downstream signalling.
Figure 2
Figure 2
Structure of LNK (SH2B3). The domain architecture of full-length LNK (right, prediction from AlphaFold) includes three functional domains. The first is a dimerisation domain, a central pleckstrin homology domain and a C-terminal SH2 domain joined by what is predicted to be unstructured regions (left). The crystal structures of the M. musculus LNK SH2 domain with JAK2 pY813 (PDB ID: 7R8W) and EPOR pY454 (PDB ID: 7R8X) peptides.
Figure 3
Figure 3
Mutations located within the LNK SH2 domain. Secondary structural elements of the LNK SH2 domain with the position of mutations identified within the SH2 domain indicated (top). Structure of the M. musculus LNK SH2 domain with the JAK2 pY813 peptide bound (PDB ID: 7R8W). Residues identified as mutation sites are shown as sticks and highlighted in pink (H. sapiens LNK SH2 domain numbers are indicated, all residues are conserved in M. musculus).
See this image and copyright information in PMC

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