Sh2b3, also known as LNK, is an adaptor protein that negatively regulates cytokine signaling and cell proliferation [1,4,5]. It is highly expressed in hematopoietic cells and is involved in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway [2,3,7]. Genome-wide association studies have linked Sh2b3 to various diseases, highlighting its biological importance. Genetic models, such as gene-knockout (KO) mouse models, have been crucial for studying its functions [4,5,6].

In KO mouse models, Lnk-deficient mice display accelerated carotid artery thrombosis with prominent neutrophil extracellular trap (NET) formation, which is OxPL-dependent, indicating its role in thrombosis [2]. In the context of hypertension, mice homozygous for the minor allele of a Sh2b3 polymorphism show higher systolic blood pressure, renal injury, and enhanced interferon gamma production due to less negative regulation of IL-12 signaling [4]. Also, Lnk -/- mice are more susceptible to atrial fibrillation, with electrical and bioenergetic remodelling [6]. In juvenile myelomonocytic leukemia, loss-of-function mutations in Sh2b3 lead to abnormal hematopoietic cell proliferation [3].

In conclusion, Sh2b3 plays essential roles in regulating cytokine signaling, cell proliferation, and is involved in multiple disease conditions such as thrombosis, hypertension, atrial fibrillation, and juvenile myelomonocytic leukemia. Studies using KO mouse models have been instrumental in uncovering these functions, providing insights into the underlying mechanisms and potential therapeutic targets for these diseases.