Sandbox Reserved 1490: Difference between revisions
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– '''Mutation in position 849 : Arginine → Tryptophane:''' Change from large size and basic (R) to large size and aromatic (W). Increased autophosphorylation and kinase activation; no effect on location at membrane. | – '''Mutation in position 849 : Arginine → Tryptophane:''' Change from large size and basic (R) to large size and aromatic (W). Increased autophosphorylation and kinase activation; no effect on location at membrane. | ||
Arginine at position 849 is found in six residues upstream of the invariant lysine K855 in the kinase domain (sequence preserved among the human, bovine, murine and rat TIE2 sequences). This seems to prove that a basic amino acid is essential for this position. In addition, arginine located a few amino acids before invariant lysine is involved in stabilizing the kinase domain (hydrogen binding of arginine with a proline downstream). It is therefore possible that R849 may also be involved in the stabilization of the kinase domain. Thus, the substitution of R849 by a W could modify the conformation of the kinase domain, leading to a decrease in inhibitory mechanisms and involving autophosphorylation. | Arginine at position 849 is found in six residues upstream of the invariant lysine K855 in the kinase domain (sequence preserved among the human, bovine, murine and rat TIE2 sequences). This seems to prove that a basic amino acid is essential for this position. In addition, arginine located a few amino acids before invariant lysine is involved in stabilizing the kinase domain (hydrogen binding of arginine with a proline downstream). It is therefore possible that R849 may also be involved in the stabilization of the kinase domain. Thus, the substitution of R849 by a W could modify the conformation of the kinase domain, leading to a decrease in inhibitory mechanisms and involving autophosphorylation.<ref>PMID:8980225</ref> | ||
[[Image:Venous Malformations Diagram.jpg]] | [[Image:Venous Malformations Diagram.jpg]] | ||
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[[Image:Venous Malformations Immunohistochemistry.jpg]] | [[Image:Venous Malformations Immunohistochemistry.jpg]] | ||
''Fig 5. Pictures of immunohistochemistry of VMs with Antibodies against Smooth Muscle Cells 𝛂-Actin <ref>PMID:8980225</ref> | ''Fig 5. Pictures of immunohistochemistry of VMs with Antibodies against Smooth Muscle Cells 𝛂-Actin <ref>PMID:8980225</ref>'' | ||
B = Abnormal channels | ''B = Abnormal channels'' | ||
C = Normal veins (v) and arteries (a) | ''C = Normal veins (v) and arteries (a)'' | ||
Scale bars, 200 𝛍m. | ''Scale bars, 200 𝛍m.'' | ||
Antibodies directed against SMCs 𝛂-Actin from cells with VMs show that the vessels have a specific and abnormal staining (B) compared to normal vessels (C)'' | ''Antibodies directed against SMCs 𝛂-Actin from cells with VMs show that the vessels have a specific and abnormal staining (B) compared to normal vessels (C)'' | ||
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[[Image:electro.png]] | [[Image:electro.png]] | ||
''Fig 6. Western blot of p-TIE2 in Human Endothelial Cells transfected with TIE2-WT (Wild type) or with mutant TIE2 (L914F). Tubulin served as loading control. The hyperphosphorylation is clearly visible.'' | ''Fig 6. Western blot of p-TIE2 in Human Endothelial Cells transfected with TIE2-WT (Wild type) or with mutant TIE2 (L914F). Tubulin served as loading control. The hyperphosphorylation is clearly visible.''<ref>PMID:26258417</ref> | ||
Thus, genetic and transplantation‐based models offer versatile tools to study the pathology of VMs, as well as the efficacy and safety of potential molecular therapies. | Thus, genetic and transplantation‐based models offer versatile tools to study the pathology of VMs, as well as the efficacy and safety of potential molecular therapies. | ||
Rapamycin is the first molecular therapy for VMs. It is currently being tested in a multicenter clinical trial on lymphatico-vascular malformations. <ref>PMID:26258417</ref> | Rapamycin is the first molecular therapy for VMs. It is currently being tested in a multicenter clinical trial on lymphatico-vascular malformations.<ref>PMID:26258417</ref> | ||
[[Image:lesion area.png]] | [[Image:lesion area.png]] | ||