SH2B adapter protein 3 (UniProt Q9UQQ2; also known as Lymphocyte adapter protein, Lymphocyte-specific adapter protein Lnk, Signal transduction protein Lnk) is encoded by the SH2B3 (also known as IDDM, LNK) gene (Gene ID 10019) in human. LNK/SH2B3 is a SH2B family adaptor protein that functions as a negative regulator in hematopoiesis and cytokine signaling mediated by Janus kinase and receptor tyrosine kinases. Originally characterized in normal and malignant hematopoeitic cells, LNK is expressed in many other tissues, including kidney, brain, and various muscle types. Evidences indicate that LNK/SH2B3 also plays a negative regulatory role in TNF- and integrin signaling and actin cytoskeleton structure in both platelets and endothelial cells, affecting cell adhesion, migration, and thrombosis. Sh2b2-knockout in mice results in splenomegaly, abnormal lymphoid and myeloid homeostasis, increased hematopoietic progenitor cells and hypersensitivity to cytokines, while SH2B3 overexpression causes impaired expansion of lymphoid precursor cells and altered mature B-cell population. In addition, human SH2B3 gene has been linked to hypertension and renal disease by genome-wide association studies (GWASs), supporting the involvement of immune-mediated mechanisms in the pathogenesis of hypertension. Human LNK is a 575aa protein that contains a dimerization domain (DD) and proline-rich regions in its N-terminal region, followed by a PH domain (a.a. 194-307) and SH2 domain (aa364-462). The DD domain possesses a phenylalanine zipper motif that mediates the formation of homo- and heterodimers between SH2-B family members.
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