Sh2b3, also known as LNK, is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. It plays a crucial role in multiple biological processes as it inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors [2,5]. It is highly expressed in hematopoietic cells and also has functions in other cell types, suggesting a broader role in the body [1]. Genetic animal models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been valuable in studying its functions.

In Lnk -/- mice (KO model), there are prominent platelet-neutrophil aggregates, accelerated atherosclerosis, and thrombosis, along with increased NETosis, which is reversed by PAD4 deficiency or the introduction of E06-scFv transgene. This indicates that hematopoietic Lnk deficiency promotes NETosis and arterial thrombosis in an oxidized phospholipid (OxPL)-dependent fashion [2]. In another study, mice homozygous for the minor allele of a SH2B3 polymorphism (Trp/Trp) show higher systolic blood pressure, exacerbated renal injury and fibrosis during angiotensin II infusion compared to the major allele (Arg/Arg) controls. This is due to less negative regulation of IL-12 signaling in CD8+ T cells by the Trp-encoding SH2B3, leading to enhanced interferon gamma (IFNγ) production [3]. Also, Lnk -/- mice display increased atrial fibrillation (AF) duration, which is prevented by a dicarbonyl scavenger. In these mice, there are pro-arrhythmic electrical and bioenergetic changes in the atria, and rs3184504 (a variant in SH2B3) is associated with AF and AF-related stroke in humans [4].

In conclusion, Sh2b3 is a key regulator of cytokine signaling, and its loss-of-function in KO/CKO mouse models reveals its important roles in diseases such as thrombosis, hypertension-related renal damage, and atrial fibrillation. These models have provided valuable insights into the pathophysiological mechanisms underlying these diseases, highlighting Sh2b3 as a potential therapeutic target.