SH2B3 is a linear DNA, (52676 bp). This gene has 3 transcripts (splice variants), with a total number of 38202 public variants reported, 202 orthologues, and 2 paralogues. Lnk’s single nucleotide polymorphisms (SNPs) are reported in exons 2, 3, and 5 and involve the Lnk PH and the SH2 domains.

This gene has 9 exons:

Exon 1: 5001-5330, size: 329 bp

Exon 2: 17172-17930, size: 758 bp

Exon 3: 33915-34080, size: 165 bp

Exon 4: 45806-45907, size: 101 bp

Exon 5: 45995-46086, size: 91 bp

Exon 6: 46178-46272, size: 91 bp

Exon 7: 46383-46597, size: 94 bp

Exon 8: 46709-46880, size: 171 bp

Exon 9: 47036-50676, size: 3640 bp

ncbi.nlm.nih.gov

This gene has 3 transcripts:

1- SH2B3-201, Transcript ID (ENST00000341259.7), 5431 bp, Protein: 575 aa

2- SH2B3-202, Transcript ID (ENST00000538307.1), 2062 bp, Protein: 373 aa

3- SH2B3-203, Transcript ID (ENST00000550925.2), 648 bp, Protein: 216 aa

www.ensembl.org

Lnk has structural similarities to the other SH2-B adaptor proteins (SH2B1 and SH2B2), which all contain the multimerization, PH, and SH2 domains. Lnk is structurally composed of several functional domains, including a carboxyl-terminal Src homology 2 (SH2) domain, which is essential for specific binding to phosphotyrosine residue, a pleckstrin homology (PH) domain, which recognize phosphoinositides and control protein translocation to the cell membrane, proline-rich regions, dimerization domain (DD) and several putative tyrosine phosphorylation motifs.

Size: 575 amino acids

Molecular mass: 63225 Da

Quaternary structure: Binds to the tyrosine-phosphorylated TCR zeta chain via its SH2 domain.

proteinatlas.org

This gene is expressed in the bone marrow & lymphoid tissues, Brain, Skin, Endocrine tissues, Lung, Proximal digestive tract, Liver & gallbladder, Kidney & urinary bladder, Female tissues (vagina, ovary, Fallopian tube, Endometrium, Placenta, breast). 

https://www.proteinatlas.org/ENSG00000111252-SH2B3

Located in cell membrane and cytoplasm.

Lnk Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2, and phosphatidylinositol 3-kinase. It blocks 3 major signaling pathways, Stat5, Akt, and MAPK, induced by Epo in primary erythroblasts. Lnk has been shown to negatively control receptors activation such as stem cell factor (SCF) receptor (c-kit), thrombopoietin receptor (MPL), erythropoietin receptor (EPOR), platelet-derived growth factor receptor (PDGFR), or more recently macrophage colony-stimulating Factor receptor (c-Fms). Phosphorylated Lnk associates with c-kit and decreases phosphorylation of Grb2-associated-binding protein 2 (Gab2) and downstream MAPK cascade (phospho-ERK1/2).

The absence of Lnk causes enhanced and prolonged TPO induction of signal transducers and activators of transcription STAT 3/5, Akt, and MAPK signaling pathways whereas Lnk overexpression in bone marrow (BM)-derived megakaryocyte decreases TPO-dependent megakaryocyte growth. Lnk blocks three major signaling pathways induced by EPO signal: Akt, STAT5, and MAPK.

Therefore, Lnk negatively modulates TPO and EPO signaling by attenuating JAK2 activation and regulates HSC self-renewal, megakaryopoiesis, and erythropoiesis.

Genetic studies reported a task for Lnk gene polymorphism and mutations in numerous diseases together with type one diabetes (T1D), hypertension, myocardial infarction, coeliac disease, myeloproliferative diseases, erythrocytosis, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis. A missense mutation at position 262 (R262W) was initially found (SNP: rs3184504). The rs3184504 marker is a non-synonymous SNP in exon 3 of SH2B3 leading to an R262W amino acid change in the pleckstrin homology (PH) domain. The Lnk R262W mutation has been found associated with autoimmune and cardiovascular disorders. A 5-bp deletion and missense mutation (NM_005475.2:c.[603_607delGCGCT; C613G]), leading to a premature stop codon. This mutation leads to the lack of both the PH and SH2 domains.