Adaptor Protein SH2NK Functions As A Negative Regulator Of The SHUK-Stta Pathway
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Adaptor protein SH2B3/LNK functions as a negative regulator of the JAK-STAT pathway. Its mutations are involved in myeloproliferative neoplasms (MPNs) and erythrocytosis that are usually associated with elevated levels of red blood cells (RBC). It is known that animals living under hypoxic conditions have high RBC. Genetic alterations in the SH2B3 gene may be an intrinsic factor. In this study, we analyzed the amino acid sequences of SH2B3 of mammals living in normoxic and hypoxic habitats in comparison with known mutations or single nucleotide polymorphisms (SNPs) in the human genome. This comparative analysis of the amino acid sequence is intended identify potential gene alterations responsible for RBC disorders.
Essential…show more content… Amino acid residues were aligned with the Mutalin software and are shown only at positions of 100% conservation Figure 3: Amino acid residues at positions 109, 180, 308, 311, 313, 315, 396, 483, and 537 show correlation between deleterious amino acid alterations, animal's habitations, and RBC levels. Highly conserved regions in SH2B3 were observed to have many amino acid alterations among hypoxic animals
Several highly conserved regions in SH2B3 were observed to have amino acid alterations among hypoxic animals.
Table 2: SNPs in the human genome for the conserved regions in the SH2B3 gene’s potential effect
Mutations to the conserved regions proved to be mostly deleterious. Table was gotten from the PROVEAN and polyphen Program.
Figure.4: Phylogram showing the relationship among hypoxic animals in comparison to human. Gene tree was deduced from the NCBI blast alignment.
The amino acid sequences of SH2B3 are conserved in mammals, especially in the SH2 domains and between the SH2 domain and the C-terminal of the gene. Potentially deleterious amino acid alterations in SH2B3 may help some animals to adapt to their hypoxic environments but may, however, lead to the development of MPNs in humans. Our data should help develop therapeutic strategies to treat RBC-related diseases. 1. Generate specific mutant forms of SH2B3 by performing site-specific mutagenesis.
2. Test the effects of the SH2B3 mutants in